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Targeting Reactive Oxygen Species in Cancer via Chinese Herbal Medicine.

1. Introduction

Reactive oxygen species (ROS) and the oxidative stress that they produce have historically been considered mutagenic and carcinogenic because they can damage macromolecules such as DNA, lipids, and proteins, leading to genomic instability and changes in cell growth [1, 2]. Thus, ROS can contribute to malignant transformation and drive tumor initiation, development, and progression. Therefore, antioxidants are usually thought to be beneficial for both the prevention and treatment of cancer because they can quench ROS and reduce oxidative stress [1]. However, many clinical studies have shown that antioxidant supplements do not reduce the risk of cancer or prevent tumor growth, sometimes even exerting the opposite effects [3,4]. Then, the protumorigenic effect of antioxidants, as well as their promotion of tumor distant metastasis, was confirmed in mouse models of cancer [5, 6]. This finding emphasized the positive role of ROS in tumor inhibition from the opposite perspective. In this context, the biological functions of ROS in cancer are rather contradictory and ambiguous [7]. As two-faced molecules, ROS not only are associated with deleterious effects but are also signaling molecules involved in multiple cellular signaling pathways important for the fate of both normal and tumor cells [8]. Thus, developing approaches for the rational use of ROS in antitumor applications is very challenging but worthwhile.

Chinese herbal medicine (CHM) has been used in China for approximately three thousand years and has contributed greatly to human health. In addition, as the main components of natural products, CHM has been regarded as an important source for novel lead compounds for the discovery of modern drugs, including anticancer drugs [9]. Currently, an increasing number of cancer patients are using CHM and its derivatives as complementary and alternative drugs; indeed, these medicines display synergistic effects when combined with conventional chemotherapy, radiation therapy, and even molecular targeted agents. Moreover, some have been suggested to have distinctive advantages in treating certain tumors [10]. A few clinical studies have reported that CHMs can alleviate the symptoms of diseases, improve the quality of life, and prolong the survival of cancer patients [11,12]. However, the underlying mechanisms remain largely unknown. Many active compounds and ingredients in CHM can exert multiple antitumor effects accompanied by changes in cellular ROS. In this article, we comprehensively reviewed the dual roles of ROS in cancers and the ROS-mediated roles of CHM in cancer progression and treatment.

2. Generation and Biological Functions of ROS

2.1. Generation of ROS. ROS are broadly defined as oxygen-containing chemical molecules with highly reactive properties and mainly include superoxide anions ([O.sub.2.sup.-]), hydrogen peroxide ([H.sub.2][O.sub.2]), and hydroxyl radicals (OH) [8, 13]. These molecules are by-products of aerobic metabolism and are mainly derived from mitochondria, peroxisomes, and the endoplasmic reticulum (ER), among which mitochondria are the major source--approximately 2% of the oxygen consumed by mitochondria is used to form the superoxide anion [14,15]. In the process of mitochondrial oxidative phosphorylation, electrons leaking from the electron transport chain (ETC) may react with molecular oxygen to produce [O.sub.2.sup.-] a reaction that is primarily mediated by coenzyme Q, ubiquinone, and respiratory complexes I, II, and III [16]. [O.sub.2.sup.-] is the precursor form of most other ROS species which can be rapidly converted to [H.sub.2][O.sub.2] by the corresponding superoxide dismutase (SOD). Further, [H.sub.2][O.sub.2] can be converted to OH' by Fenton chemical reactions in the presence of a metal (iron or copper) (Figure 1). In addition to mitochondria, NADPH oxidases (NOXs) are another prominent source of superoxide that can catalyze the formation of [O.sub.2.sup.-] from [O.sub.2] and NADPH (Figure 1). Besides, ROS are formed in the cytoplasm by enzymatic reactions involving peroxisomes, xanthine oxidase, cytochrome P450, lipoxygenases (LOXs), and cyclooxygenases.

Intracellular ROS levels are tightly controlled via diverse, complex synthesis and degradation pathways; this tight control is crucial for cellular homeostasis (Figure 1). The ROS-detoxifying system mainly comprises both enzymatic and nonenzymatic antioxidants [7, 17]. Enzymatic antioxidants include SOD, catalase (CAT), glutathione peroxidase (GPX), peroxiredoxin (PRX), and thioredoxin (TRX); nonenzymatic antioxidants include glutathione (GSH), flavonoids, and vitamins A, C, and E [18]. As described above, SOD can rapidly catalyze the conversion of [O.sub.2.sup.-] to [H.sub.2][O.sub.2], which can be further converted to water by the PRX system, the GPX system, and CAT. SOD has three isoforms in mammals: cytoplasmic Cu/ZnSOD (SOD1), mitochondrial MnSOD (SOD2), and extracellular Cu/ZnSOD (SOD3), all of which require specific catalytic metals (Cu or Mn) for activation [19]. PRXs are considered ideal [H.sub.2][O.sub.2] scavengers due to their abundant expression and broad distribution in cellular compartments such as the cytosol, the ER, mitochondria, and peroxisomes. During the metabolism of [H.sub.2][O.sub.2], PRX is oxidized and subsequently reduced by TRX, which is then reduced by thioredoxin reductase (TrxR) via the transfer of electrons from NADPH [20]. In addition to PRXs, GPXs are important scavengers. GPX catalyzes the reduction of [H.sub.2][O.sub.2], leading to the oxidation of GSH to glutathione disulfide (GSSG) that can be reduced back to GSH by glutathione reductase (GR) with NADPH as an electron donor [21].

In addition to antioxidant enzymes, the transcription factor nuclear factor erythrocyte 2-related factor 2 (Nrf2) plays a vital role in regulating the intracellular redox status [17]. Under physiological conditions, Nrf2 is located in the cytoplasm and remains at a low level under the control of Kelch-like ECH-associated protein 1 (KEAP-1). KEAP binds and specifically degrades Nrf2 via the ubiquitin-proteasome pathway. Under oxidative stress, Nrf2 dissociates from KEAP and is translocated to the nucleus. Then, activated antioxidant response elements (AREs), such as GSH, TRX, and PRX, decrease the intracellular ROS levels and protect against cell death [22] (Figure 1).

2.2. Biological Functions of ROS. A canonical mechanism by which ROS participate in the regulation of redox signaling is through the oxidative modification of cysteine residues in proteins [16]. During the redox process, reactive cysteine thiol (Cys-SH) can be oxidized by [H.sub.2][O.sub.2] to reversible sulfenic acids (Cys-SOH), resulting in allosteric and functional changes within the protein [8]. This process is reversible; Cys-SOH can be reduced to its original state and restored its function by the TRX and GRX [8, 18]. Meanwhile, Cys-SOH can be further oxidized by continuously elevated ROS to form irreversible oxidation products, such as sulfinic or sulfonic species, causing permanent oxidative damage to proteins. This accounts for the double-sided nature of ROS and to a large extent, depending on its intracellular concentration and duration of exposure.

ROS involve a series of biological effects that are concentration-dependent. At low to moderate levels, ROS function as a second messenger and are involved in mediating cell proliferation and differentiation and the activation of stress-responsive survival pathways by regulating various cytokine receptors, serine/threonine kinase receptors, and G protein-coupled receptors [23, 24]. In contrast, due to their strong oxidizing capacity, ROS at a high level can react with intracellular macromolecules such as phospholipids, nucleic acids, and proteins to produce cytotoxicity. ROS have been linked to many diseases, such as cancers and diabetes [25]. The tight modulation of both ROS-producing pathways and ROS-detoxifying pathways may be required for the control of these diseases [26].

3. ROS and Cancer

The dual properties of ROS described above are simultaneously utilized by normal cells and cancer cells to support cell growth and survival. However, most cancer cells have higher levels of ROS than normal cells due to their enhanced glucose metabolism (the Warburg effect), mitochondrial dysfunction, and oncogenic activity [18, 27]. On one hand, this property enables the activation of central protumorigenic signaling pathways. On the other hand, the resulting oxidative stress may also exert potential antitumor effects [8]. In the next sections, we discuss how ROS can either promote or inhibit cancer progression, providing the clues for anticancer therapies based on redox regulation.

3.1. Pros of ROS in Cancer. Moderately increased levels of ROS are a pivotal driving factor of tumor initiation, development, and progression [24,26] (Figure 1). In the initial stage of tumor formation, ROS may function as a direct DNA mutagen, induce genomic instability, damage mitochondrial DNA, and activate various signaling cascades to trigger malignant transformation [28-31]. In addition to causing significant genetic changes, ROS may alter the expression of oncogenes or tumor suppressor genes by mediating epigenetic modifications such as methylation or acetylation, thereby promoting carcinogenesis [32]. Conversely, these events may, in turn, promote ROS production and accumulation, leading to further oxidative DNA damage and the malignant deterioration of cells to aid tumor formation [28, 32].

Existing tumors exhibit several noticeable characteristics, including sustained proliferation, apoptosis resistance, angiogenesis, invasion and metastasis, and tumor-promoting inflammation [33]. ROS are involved in all of these processes, which are conducive to tumor survival and development. ROS regulate the activities of many proteins and signaling pathways, thereby facilitating tumor cell proliferation and death evasion. For example, ROS can transiently inactivate tumor suppressors such as phosphatase and tensin homologue (PTEN) [34], protein tyrosine phosphatases (PTPs) [35], and MAPK phosphatases [36] by oxidative modulation, thereby stimulating the prosurvival PI3K/AKT and MAPK/ERK signaling pathways. Importantly, multiple transcription factors, such as activator protein 1 (AP-1), nuclear factor-[kappa]B (NF-[kappa]B), Nrf2, and hypoxia-inducible factor-1[alpha] (HIF-1[alpha]), which are involved in the control of genes in cell proliferation, are also regulated by increased levels of ROS [37].

Tumor-associated neovasculature formation, or angiogenesis, provides oxygen and nutrients for the continued growth of cancer cells and is a key step in tumor growth and metastasis [38]. A wealth of evidence has shown that ROS play an essential role in tumor angiogenesis through mediating the following events. ROS, especially [H.sub.2][O.sub.2] derived from NOXs, selectively promote endothelial cell (EC) proliferation and survival [39] and prevent apoptosis. Furthermore, ROS-mediated cadherin/catenin phosphorylation leads to the disassembly of EC junctions and promotes cell migration [40, 41]. Additionally, ROS activate VEGF signaling via multiple pathways, including through the induction of the principal regulator HIF-1[alpha], which increases VEGF and VEGFR expression [42], and, as mentioned before, through the induction ofthe PI3K/Akt and MAPK pathways, which activates angiogenic signaling cascades for the upregulation of VEGFR expression. Consistent with this pattern, an increase in the level of extracellular SOD may also suppress the hypoxic accumulation of HIF-1[alpha] and its downstream target gene VEGF in several different types of cancer cells [43, 44].

Metastasis is a ubiquitous event in cancer development and encompasses a wide array of cellular changes, including the loss of cell-to-cell adhesion, the survival of cells upon matrix detachment, and the ability of cells to migrate and penetrate the basement membrane; ROS are involved in all of these processes [16, 45]. Indeed, ROS generated from NOXs are necessary for invadopodium formation and function in Src-transformed cell lines [46]. Similarly, ROS enable the direct oxidation of the protein tyrosine kinase Src, thereby enhancing the invasive potential, anchorage-independent growth, and survival of Src-transformed cells [47]. Furthermore, [H.sub.2][O.sub.2] has been demonstrated to activate FAK in a PI3 kinase-dependent manner to accelerate cell migration [48]. ROS also participate in the abnormal activation of many proteolytic enzymes, such as MMP, uPA, and cathepsins, facilitating cell migration [49,50]. Several tumor invasion signaling pathways upstream of MMPs and uPAs, such as the MAPK, PI3K/Akt, and PKC pathways and those modulated by defined transcription factors (AP-1 and NF-[kappa]B), are modulated by ROS [50,51]. Besides, ROS may induce the expression of transcription factors such as Snail and HIF-1[alpha] [52], leading to epithelial to mesenchymal transition (EMT), an aggressive behavior favoring cancer metastasis and involved in drug resistance[53, 54].

3.2. Cons of ROS in Cancer. As stated earlier, cancer cells exhibit higher levels of ROS than normal cells, which contributes to tumor formation and development. However, excessive high levels of ROS can block cell cycle and induce different types of cell death, including apoptosis, autophagic cell death, ferroptosis and necroptosis. Due to space limitations, we focus on the first three types of cell death.

Apoptosis is the most common form of programmed cell death (PCD) in multicellular organisms with typical morphological and biochemical features. Also, apoptosis is a highly regulated process in which cells undergo self-destruction. The two well-known signaling mechanisms are the extrinsic death receptor pathway and the intrinsic mitochondrial pathway. ROS have been demonstrated to be implicated in the activation of both [55, 56]. ROS can activate the transmembrane death receptors such as Fas, TRAIL-R1/2, and TNF-R1 and then recruit the adaptor proteins FADD and procaspase-8/-10 to form death-inducing signaling complexes (DISCs), subsequently triggering the caspase activation and apoptosis [55]. Besides, ROS have been shown to posttranscriptionally inhibit c-FLIP, which suppresses DISC formation, thus causing the activation of the extrinsic apoptosis pathway [57]. Alternatively, ROS may activate ASK1 by oxidizing Trx, resulting in the subsequent induction of apoptosis through MAPKs such as JNK/p38 [58].

In the intrinsic apoptosis pathway, ROS at an elevated level destroy mitochondrial membranes, causing the release of cytochrome c from mitochondria and the induction apoptosis [18, 59]. Cytochrome c forms an apoptotic complex with apoptotic protein activating factor 1 (Apaf-1) and precaspase 9, resulting in the activation of caspase-9, followed by the induction of effector molecules such as caspase-3/7 [60]. The substantial loss of cytochrome c from mitochondria further increases ROS generation due to the disruption of the mitochondrial ETC [55]. Furthermore, ROS have been shown to regulate the activities of both antiapoptotic (Bcl-2, Bcl-X, and Bcl-wl) and proapoptotic (Bad, Bak, Bax, Bid, and Bim) Bcl-2 family proteins, which play an essential role in regulating the intrinsic pathway of apoptosis [61, 62].

In addition, ROS may act as upstream signaling molecules through the ER pathway, another important intrinsic apoptosis pathway. ROS at an excessive level trigger protein misfolding, leading to the unfolded protein response (UPR) and the induction of CHOP, thereby initiating apoptosis by regulating the expression of Bcl-2 family genes [63]. Moreover, ROS can stimulate the release of [Ca.sup.2+] in the ER lumen [64]. Due to the proximity of mitochondria to the ER, when a large amount of [Ca.sup.2+] is released from the ER, a substantial amount of [Ca.sup.2+] is absorbed by mitochondria, causing [Ca.sup.2+] overload in mitochondria. This leads to stimulating the opening of mitochondrial permeability transition pores (MPTPs) leading to the release of ATP and cytochrome c, which further enhance apoptosis and increase ROS generation [65, 66]. Besides, ER stress-mediated apoptosis is partly controlled by the ASK-1/JNK cascade, which is directly regulated by ROS, as mentioned above.

Autophagy (macroautophagy), which is considered a cell survival mechanism to maintain cellular homeostasis, is multistep characterized by the formation of double-membrane autophagosomes by which cells utilize lysosomes to degrade and recycle their damaged organelles and macromolecules [67]. However, depending on the context, autophagy can function as a cell death mechanism and a tumor suppressor mechanism [68]. Many anticancer agents can induce autophagy in cancer cells. Some of them can induce ROS-dependent autophagy leading to cell death (autophagic cell death) [20, 69, 70].

ROS appear to be a key regulator of autophagy under different conditions and are involved in both the protective and toxic effects of autophagy [71]. Currently, several significant mechanisms by which ROS affect autophagy have been revealed. Under starvation conditions, [H.sub.2][O.sub.2] can oxidize and inactivate ATG4, thereby contributing to the increased formation of LC3-associated autophagosomes [72]. ROS may directly trigger the oxidation of ATM to induce AMPK phosphorylation, which inhibits mTORC1 activation and phosphorylates the ULK1 complex to induce autophagy [73-75]. Also, AMPK can be phosphorylated by its upstream kinase AMPK kinase (AMPKK), leading to the induction of autophagy. In an alternative mechanism, [H.sub.2][O.sub.2] activates Bcl-2/E1B interacting protein 3 (BNIP3) to suppress the activity of mTOR and abolish the interaction between Beclin-1 and Bcl-2, causing Beclin-1 release and autophagy induction [76, 77]. Besides, ROS can modulate autophagy by affecting the activity of various transcription factors such as NF-[kappa]B, resulting in the expression of autophagy-associated genes (BECN1/ATG6 or SQSTM1/p62) in cancer cells [78, 79].

In contrast, autophagy can reduce ROS levels through the NRF/KEAP1 and P62 pathways [80]. In response to ROS, P62 is activated and thus interacts with KEAP1 to contribute to the suppression of NRF2 degradation and the promotion of its activation, which, in turn, can activate antioxidant defense genes such as GPX, SOD, and TRX [79, 81]. This process contributes to the regulation of autophagy.

Ferroptosis, first named by Dixon et al. in 2012, is emerging as a new form of PCD characterized by the accumulation of cellular ROS in an iron-dependent manner [82, 83]. Ferroptosis is primarily caused by an imbalance in the production and degradation of intracellular lipid ROS and can cause iron-dependent oxidative cell death through a reduction in antioxidant capacity and an accumulation of lipid ROS. Many compounds can induce ferroptosis to kill cancer cells in a manner mainly related to the metabolism of amino acids/GSH, lipids, and iron and the regulation of P53 [84].

Erastin can inhibit the activity of the cysteine-glutamate antiporter (system [X.sub.C.sup.-]), reduce cystine uptake, and lead to the associated depletion of intracellular GSH, in turn causing toxic lipid ROS accumulation and ferroptosis [82, 85]. Inhibition of glutathione peroxidase 4 (GPX4), a GSH-dependent enzyme required for the elimination of lipid ROS, can trigger ferroptosis even at regular cellular cysteine and GSH levels [86]. Other lipophilic antioxidants, such as Trolox, ferrostatin-1, and liproxstatin-1, can inhibit ferroptosis [82, 87]. Intracellular iron is another essential regulator of lipid ROS production and ferroptosis induction. In the presence of iron, lipid hydroperoxides are converted into toxic lipid free radicals, leading to lipid oxidative damage and cell death [88,89]. Indeed, various iron chelators such as deferoxamine and ciclopirox can abolish ferroptotic cell death caused by system [X.sub.C.sup.-] inhibitors, GPx4 inhibitors, and GSH depletion [83]. Consistent with this observation, silencing TFRC, thus inhibiting the transport of iron into the cytoplasm, can antagonize erastin-induced ferroptosis [90]. Additionally, PKC-mediated HSPB1 phosphorylation inhibits ferroptosis by reducing the production of iron-dependent lipid ROS, but inhibition of HSF1-HSPB1 pathway activity and HSPB1 phosphorylation increases the anticancer activity of erastin [91]. Together, these results demonstrate the importance of lipid ROS and iron in promoting ferroptosis.

Recent studies have revealed a new mechanism by which P53 acts as a tumor suppressor gene to inhibit tumors by inducing ferroptotic cell death. Jiang et al. demonstrated that P53 could downregulate the expression of SLC7A11, thereby preventing system [X.sub.C.sup.-] from absorbing cystine, resulting in decreased cystine-dependent GPX activity and cellular antioxidant capacity, in turn leading to ROS-induced ferroptosis and tumor suppression [92]. Indeed, this finding is contrary to those of many other reports showing that P53 can reduce cellular levels of ROS. When ROS levels are low, P53 may prevent the accumulation of ROS from promoting cell survival, whereas when ROS levels are excessive, P53 may evoke cell death via ferroptosis. Currently, P53 is reported to exert a complex and dynamic regulatory effect on ROS, but the role of this regulation in tumors needs further study [93].

4. Anticancer Effects of CHM via ROS

As described above, ROS have dual roles in tumor suppression and tumor promotion depending on their concentrations. Moreover, most cancer cells have higher basal levels of ROS than normal cells, which is beneficial for their survival and development. In response to their high basal levels of ROS, the antioxidant capacity of cancer cells is upregulated to maintain redox balance and prevent ROS levels from excessively increasing to induce cell death [8, 26]. However, this effect is very limited in tumor cells. Therefore, either increasing or reducing ROS can be an effective strategy in cancer therapy by disrupting redox balance in tumor cells [17, 20]. CHM has a long history of treating various diseases and is becoming an integral part of comprehensive cancer treatment in China. According to the literature, CHM plays a significant role in cancer therapy through several aspects: reducing inflammatory and infectious complications surrounding the tumors, protecting normal tissues from the possible damage caused by chemo/radiotherapy, enhancing the potency of chemo/radiotherapy and molecular targeted therapies, improving immunity and body resistance to disease, improving general condition and quality of life, and prolonging the survival of advanced cancer patients [94]. However, in most cases, the chemical and pharmacological mechanisms of CHM are ambiguous. The majority of researches on the molecular mechanism of CHM were carried out with an active monomer or crude extract of a single herb, and results indicate that the anticancer activities of diverse CHMs are associated with ROS regulation. Therefore, we summarize current data regarding the ROS-related anticancer effects of CHM on the prevention and therapy of cancers. Some typical Chinese herbal compounds and ingredients are discussed. For additional examples, please see the Tables 1 and 2.

4.1. Antioxidant Effects of CHM in Cancer Progression. Carcinogenesis is a multistep process in which various genetic and epigenetic events occur through the stimulation of numerous inflammatory mediators and ROS production, resulting in the conversion of normal cells into cancer cells [1]. Many carcinogens, such as irradiation, UV light, and toxins, are also exogenous ROS inducers that accelerate the malignant transformation and promote tumor progression by increasing intracellular oxidative damage and activating cancer-promoting signals. Thus, approaches to enhance the antioxidant enzyme system or reduce ROS generation can be used to prevent tumorigenesis and slow tumor progression (Figure 2). There is a beneficial inverse relationship between the consumption of fruits and vegetables and the risk of lung cancer, due to the high antioxidant content of these foods [95, 96]. Increasing types of CHM-derived bioactive ingredients or crude extracts have been shown to suppress chronic inflammation of tissues and prevent carcinogenesis. This effect, to a certain extent, is attributed to the fact that such CHMs are homologous to food and are rich in antioxidants such as saponins, flavonoids, and polysaccharides, which can reduce the oxidative damage caused by excess ROS in normal cells [97].

Studies have shown that the overproduction of ROS induced Cr(VI)-mediated carcinogenesis. Quercetin, one of the most abundant dietary flavonoids in fruits, vegetables, and many CHMs such as Hippophae fructus (Sha Ji) and Lycii fructus (Gou Qi Zi), has potent antioxidant and chemopreventive properties [98]. Quercetin can protect human normal lung epithelial cells (BEAS-2B) from Cr(VI)-mediated carcinogenesis by targeting miR-21 and PDCD4 signaling, reducing ROS production [98]. Purslane polysaccharides (PPs), a principal bioactive constituent of the Portulaca oleracea L. (Ma Chi Xian), possess a wide range of antioxidant, immunomodulatory, and antitumor activities. Methylnitronitrosoguanidine (MNNG) is a carcinogen and mutagen commonly used in experiments. A recent study showed that PPs provide dose-dependent protection against MNNG-mediated oxidative damage by increasing the activity of SOD, CAT, and GSH-Px in gastric cancer rats [99].

During tumor growth, ROS are continuously accumulated by the stimulation of various growth factors and hypoxia-inducing factors in the microenvironment, which in turn accelerates the progression of the tumor and maintain typical hallmarks of cancer. Some CHMs can inhibit tumor growth and progress by reducing ROS production in vitro and in vivo using a mouse model. Forsythia suspensa (Lian Qiao), one of the most fundamental medicinal herbs in China, has extensive pharmacological activities and is generally used to treat infectious diseases of the respiratory system. In the past decades, its antineoplastic activity has attracted more attention. Forsythia fructus aqueous extract (FAE), as the primary bioactive ingredient of Forsythia suspensa, has shown distinct anticancer properties both in vitro and in vivo. FAE can inhibit proliferation and angiogenesis of melanoma cells by antioxidant and antiinflammatory mechanisms such as in reducing ROS, malondialdehyde (MDA), and IL-6 levels and in increasing GSH, Nrf2, and HO-1 expression [100]. Similarly, andrographolide (AP), a bioactive compound present in the medicinal plant Andrographis paniculata (Chuan Xin Lian), possesses several beneficial properties, including anti-inflammation, antioxidation, and antitumor activities. AP can antagonize TNF-[alpha]-induced IL-8 release by inhibiting the NOX/ROS/NF-[kappa]B and Src/MAPKs/AP-1 signaling pathways, subsequently suppressing angiogenesis in colorectal cancer cells [101]. Isoliquiritin (ISL) is a natural chalcone flavonoid derived from licorice compounds and has antioxidant and antitumor properties. Previous studies have demonstrated that ISL may selectively inhibit prostate cancer cell proliferation by decreasing ROS levels, thus blocking AMPK and ERK signaling [102]; furthermore, this compound can suppress the invasion and metastasis of prostate cancer cells possibly via decreased JNK/AP-1 signaling [103]. Abnormal cell energy metabolism is one of the core hallmarks of cancer [33]. Resveratrol (RSV) is a polyphenolic compound present in many types of fruits, vegetables, and Chinese medical herbs. Numerous studies have shown that it has a variety of biological and pharmacological activities, such as antioxidant, antiinflammatory, antiaging, and antitumor. RSV can inhibit invasion and migration by suppressing ROS/miR-21-mediated activation and glycolysis in pancreatic stellate cells (PSCs) [104].

In addition, ROS are involved in the antitumor activity of many chemotherapeutic agents, small molecular targeted drugs, and radiation therapy, as well as their side effects [105, 106]. The rational use of the antioxidant effects of CHMs can relieve the toxic side effects of chemo- and radiotherapy on normal cells by eliminating excessive ROS. Sulforaphane is a component of cruciferous vegetables and some Chinese medicinal plants [107]. Studies have shown that sulforaphane is a powerful natural antioxidant to prevent, delay, and improve some side effects of chemotherapy. Sulforaphane can result in the high expression of HO-1 by activating the KEAP1/NRF2/ARE signaling pathway, which protects myocardial cells from doxorubicin-induced oxidative injury and protects the gastric mucosa against H. pylori-induced oxidative damage [107, 108]. Ginseng is often used alone or in combination with other herbs for the adjuvant treatment of tumors [109]. Ginsenoside is the main pharmacologically active ingredient of ginseng in exerting anticancer activity. As the primary active component, ginsenoside Rg3 can mitigate doxorubicin-induced cardiotoxicity by ameliorating mitochondrial function, improving calcium handling, and decreasing ROS production [109]. Furthermore, Rg3 inhibits gemcitabine-induced resistance by eliminating ROS, downregulating NF-[kappa]B and HIF-1[alpha]-mediated PTX3 activity [110]. Ginsenoside Rg1 is another ingredient of ginseng and was found to alleviate cisplatin-induced hepatotoxicity via restraining the binding of Keap1 to Nrf2, partly via p62 accumulation, and enhancing Nrf2-related antioxidant activity [111]. Schisandra sphenanthera extract has a protective effect against cisplatin-induced nephrotoxicity by activating the Nrf2-mediated defense response, thus increasing GSH levels and reducing ROS levels [112]. Astragalus has a long history of treating immunodeficiency diseases in China and beyond and is often used to reduce side effects caused by chemotherapy [113]. Astragaloside IV (As-IV) is a natural saponin extracted from Astragalus membranaceus, which has antioxidant, anti-inflammatory, and antiapoptotic effects. Studies showed that As-IV markedly ameliorates BLM-induced pulmonary fibrosis in mice, an effect associated with its antagonism of bleomycin-induced oxidative stress and inflammatory responses, increasing SOD activity and total antioxidant capacity in lung tissue and reducing ROS, MDA, and IL-1[beta] levels [113].

Notably, some compounds or ingredients of CHM are generally considered to be antioxidants but can induce prooxidant effects similar to those of antioxidant supplements such as vitamin C [114]. These substances exhibit antioxidant activity at low concentrations but induce ROS production and cytotoxicity at high concentrations [115]. For example, the previously mentioned antioxidant ISL initially decreased the levels of ROS in HepG2 cells in a time-dependent manner; along with this effect, the activity of the Nrf2-mediated antioxidant enzyme system also declined to maintain the new redox balance. However, the intracellular ROS level was significantly higher after 6 h of ISL treatment, an effect attributed to reduced antioxidant capacity, and the sensitivity of cancer cells to X-ray irradiation was thus increased [115]. Epigallocatechin gallate (EGCG) is a phenolic compound in green tea extract and has anticancer activities in vivo and in vitro [116]. EGCG can decrease lipid peroxidation in hepatocytes and enhance antioxidant capacity. However, high concentrations of EGCG destroy the mitochondrial membrane and generate intracellular oxidative stress [117]. Thus, whether EGCG exhibits antioxidant or prooxidant activity depends on the cellular stress conditions, cell type, and EGCG concentration [116, 118]. CHM-derived compounds such as quercetin, curcumin, and resveratrol were found to exhibit similar features [3, 119].

To sum up, the antioxidant effects of CHMs described above and the examples listed in Table 1 exhibit diverse anticancer effects, including reducing inflammatory mediators, inhibiting tumor proliferation, inducing antiangiogenesis, suppressing metastasis, inhibiting glycolysis, overcoming drug resistance, and countering the side effects of chemoand radiotherapy. These effects were mainly achieved by the regulation of several ROS-related transcription factors such as NRF2, NF-[kappa]B, COX-2, STAT3, and HIF-1[alpha] and by enhancing the capacity of antioxidant enzymes such as GSH, SOD, and HO-1.

4.2. Prooxidant Effects of CHM in Cancer Progression. Since the levels of ROS in tumor cells are higher than those in normal cells, tumor cells are potentially more vulnerable to the accumulation of ROS. The strategy of increasing intracellular ROS levels by increasing ROS production and/or inhibiting the antioxidant capacity enables the ROS level to reach the toxic threshold in cancer cells before it does in normal cells, thereby selectively killing tumor cells without causing visible damage to normal cells (Figure 2).

Many CHM compounds can promote the production of intracellular ROS to induce various types of programmed cell death and enhance the efficacy of chemo- and radiotherapy. Scutellaria (Huang Qin) is one of the most commonly used CHMs in China and its surrounding areas and has a practical effect on infectious diseases caused by bacteria and viruses [120]. As a principal bioactive constituent of Scutellaria, wogonin has apparent anticancer effects against different types of cancer cells. It can induce mitochondrial apoptosis by activating PLC[gamma]1 via [H.sub.2][O.sub.2] signaling in malignant T cells, resulting in [Ca.sup.2+] overload in mitochondria [120]. Furthermore, wogonin enhanced TRAIL-induced apoptosis through ROS-mediated downregulation of the cFLIPL and IAP proteins [121]. In addition, levistolide A (LA), a natural compound isolated from the Chinese herb Ligusticum chuanxiong Hort., can trigger ER stress-induced apoptosis by activating the ROS-mediated PERK/eIF2[alpha]/CHOP axis [122]. Besides, LA synergizes with vinorelbine against tumors and induces cell cycle G2/M arrest and apoptosis; interestingly, it can reverse P-glycoprotein-mediated multidrug resistance in breast cancer cells [123]. Other classical compounds of CHM that target the apoptotic signaling pathway have been reviewed [9]. Sanguinarine (SNG) is a benzophenanthridine alkaloid that is predominantly extracted from Chelidonium majus (Bai Qu Cai), a well-known CHM mainly used for digestive and respiratory inflammatory diseases and malignant tumors. SNG has diverse biological activities, such as antimicrobial, anti-inflammatory, and antitumor properties. Our previous study has shown that SNG successfully inhibited the proliferation of specific lung cancer cells expressing stem cell characteristics, possibly by downregulating WNT/[beta]-catenin signaling [124]. SNG can not only induce apoptotic cell death but also trigger autophagic cell death by the ROS-dependent activation of ERK1/2 in malignant glioma cells [125]. Besides, this compound can upregulate NOX3 and then elevate ROS levels, resulting in EGF[R.sup.T790M] degradation to overcome tyrosine kinase inhibitor (TKI) resistance [126]. Artesunate is a derivative of the natural compound artemisinin, which is known for its antimalarial agents, with well-understood pharmacokinetics. ART specifically induces PCD in different cancer types in a manner initiated by ROS generation [127]. Recent studies have found that ART specifically induces ferroptotic cell death in pancreatic cancer cells in a ROS- and iron-dependent manner and that this induction can be blocked by the ferroptosis inhibitor ferrostatin-1 [128]. Interestingly, dihydroartemisinin (DAT), another artemisinin derivative with high bioavailability, enhances the sensitivity of cancer cells to ferroptosis inducers in a lysosome-dependent, but autophagy-independent manner. Importantly, DAT can further improve the ferroptosis-resistant cancer cell lines more sensitive to ferroptotic death, which suggests that the combination of DAT and ferroptosis inducers is an effective anticancer method [129].

In addition to directly inducing ROS production, inhibiting the activity of antioxidant enzymes to increase ROS levels is another potentially more effective approach to kill cancer cells. Cancer cells tend to have higher antioxidant capacity than normal cells to adapt to elevated levels of ROS, which promotes cancer cell resistance to exogenous ROS-inducing agents [119]. Many antioxidants, such as GSH, TRX, and SOD, and Nrf2 activity aid tumorigenesis and confer chemoresistance and are present at high levels in various tumor types [130-133].

Piperlongumine (PL) is a natural constituent of the long pepper fruit (Piper longum), which is extensively used in digestive diseases such as gastrointestinal cancer. PL can selectively kill a variety of tumor cells and enhance cisplatin-mediated anticancer activity [134,135]. Its anticancer effects are mainly attributed to the silencing of the GSTP1 gene, thus reducing GSH content [136]. Isoforretin A (IsoA) is a novel ent-kaurane constituent isolated from a traditional Chinese medicinal herb of the Isodon genus and has multiple anticancer effects both in vitro and in vivo. IsoA inhibits Trx1 activity by covalently binding to the Cys32/Cys35 residues in the Trx1 activation site, resulting in ROS accumulation and causing DNA damage and apoptosis in tumor cells. It can be a potential novel agent for cancer therapy [137]. Consistent with this effect, both shikonin [138, 139] and parthenolide [140] can inhibit TrxR, interfere with redox balance, and eventually lead to ROS-mediated tumor cell death. Brusatol (BR), the main active ingredient of the Brucea javanica plant, has many anticancer properties [141]. BR is a potent inhibitor of Nrf2 and can degrade Nrf2 by ubiquitination to suppress the Nrf2-dependent protective response and thus sensitize lung cancer cells to cisplatin [142]. Moreover, the combination of BR and UVA irradiation increases ROS-induced cell cycle arrest and cellular apoptosis and inhibits melanoma growth by regulating the AKT-Nrf2 pathway in cancer cells [143].

Summarizing the above examples of prooxidant CHM and those listed in Table 2, contrary to the antioxidant effects of CHM, it can be concluded that the prooxidant effects of CHM in cancer cells are achieved by enhancing ROS production and/or inhibiting antioxidant capacity, thereby activating ROS-dependent killing patterns on cancer cells. So far, the killing model of prooxidant CHM is mainly induced by apoptosis, which is primarily achieved by the regulation of ROS-related apoptotic upstream signaling pathway, such as MAPK/JNK/p38, JAK/STAT, PI3K/AKT, and ER stress pathways, followed by activation of apoptotic executive molecules, such as BAX/BCL-2, caspase family, and PARP-1. Other than this, CHMs also induce autophagic cell death, necroptosis, and ferroptosis in uncommon ways, but underlying molecular mechanisms remain unclear. Of note, ferroptosis, as a newly discovered type of cell death, possibly provides a promising choice for the application of CHM in cancer therapy, especially in the case of many conventional agents with apoptosis resistance.

5. Discussion

Cancer cells exhibit higher levels of ROS than normal cells [18, 27, 144]. ROS promote tumorigenesis via malignant transformation, sustained proliferation, angiogenesis, invasion, and metastasis. On the other hand, ROS at elevated levels can increase the vulnerability of cancer cells to various inducers. Considering the dual nature of ROS and the complexity of tumors themselves, exploring approaches to rationally utilize CHM to regulate ROS may maximize the anticancer functions of CHM.

The first strategy is to exploit the antioxidant properties of CHMs to reduce excessive intracellular ROS and to antagonize ROS-induced protumorigenic effects on normal cells. However, many clinical trials have inconsistently concluded that antioxidant supplements are beneficial for preventing tumors; furthermore, the long-term use of certain antioxidant supplements may even increase the incidence of some tumors and overall mortality [3,145]. Moreover, recent studies have shown that antioxidants can promote carcinoma proliferation and distant metastasis in vivo [6, 146]. In terms of cancer treatment, antioxidant supplements may reduce the side effects of chemo- and radiotherapy in some cases but may also antagonize the positive effects of these treatments [17,147,148]. Therefore, although the abovementioned antioxidant CHM compounds or their active ingredients have shown an initial positive effect in tumor prevention and have been shown as an adjuvant treatment in preclinical studies, caution must be taken in their long-term application. Antioxidant CHMs are different from antioxidant supplements due to the fact that they are natural products with a complex combination of active ingredients. The properties of antioxidant CHMs are closer to those of fruits and vegetables rich in antioxidants. Thus, the use of CHMs rich in antioxidants rather than a single antioxidant compound might have better effects in tumor prevention. However, further systematic studies are needed.

Compared to ROS reduction strategies, which have a controversial role in application to tumors, ROS promotion strategies have shown better anticancer effects and clinical prospects. Such strategies can be implemented by using an agent that either increases ROS production or reduces antioxidant capacity or results in a combination of both effects. Various chemotherapeutic drugs, molecular targeted drugs, radiotherapy, and photodynamic therapy have been shown to kill tumor cells by increasing intracellular ROS levels [56, 104, 149, 150]. To date, some novel ROS inducers (such as ARQ501 and elesclomol), as well as antioxidase system drugs (such as the SOD1 inhibitor ATN-224 and the GSH inhibitors buthionine sulfoximine (BSO) and phenethyl isothiocyanate (PEITC)), have also been under clinical trials (see Many CHM-derived active constituents act as ROS generators to exert anticancer effects. Importantly, the intracellular level of ROS should be carefully controlled when using ROS-generating CHMs. If the levels of ROS are not sufficiently increased to the toxicity threshold, downstream oncogenes, such as PI3K, HIFs, NF-[kappa]B, and MAPK, may be activated to promote cancer development. Conversely, increasing the ROS levels too far over the cytotoxic level will lead to nonspecific damage to normal cells, thereby injuring sensitive vital organs such as the heart, liver, and kidneys [8]. Indeed, tumor cells maintain elevated antioxidant system activity to prevent oxidative damage from cytotoxic ROS; thus, ROS generators are not always useful. However, the use of antioxidant inhibitors in combination with ROS inducers may be a promising method in anticancer therapy because this approach can decrease the adaptability of tumor cells to both agents [20, 26]. Compounds such as curcumin [151] and triptolide [152] can simultaneously induce ROS generation and inhibit antioxidant defense, causing cancer cell death and enhancing the efficacy of chemotherapy. This pleiotropic effect may be beneficial in overcoming the resistance of cancer cells to conventional single-target drugs [149]. However, due to the bimodal nature of ROS and CHM, identifying the specific types of ROS and antioxidant molecules that are uniquely required for tumor growth and survival and determining the mechanisms targeted by the specific CHM in different types of tumors are important. Currently, the advent of new molecular tools for the localization, quantification, and real-time detection of ROS is expected to further deepen our understanding of redox, to advance ROS-based treatment strategies, and to generate great opportunities for the development of anticancer drugs from CHMs.

6. Conclusions

In summary, we describe how ROS are generated and eliminated within cells and the complicated dual roles of ROS in cancers. ROS not only are indiscriminate damaging molecules but also function as specific secondary messengers, involved in various physiological and pathological responses. This is the current focus on the debate in the field of redox biology and accounts for inconsistency with clinical and experimental studies on ROS. Traditional Chinese medicine is an ancient practice medicine with potential advantages in cancer treatment. We selected and summarized the original researches of CHM based on ROS regulation with relatively precise molecular mechanisms. CHMs exert antitumor effects through antioxidant activities, including inhibition of inflammation; prevention of carcinogenesis; inhibition of tumor proliferation, growth, and metastasis; and reduction of side effects of chemo- and radiotherapy; on the other hand, CHMs primarily induce multiple cell death to kill cancer cells selectively by promoting oxidation, cause DNA damage and enhance the efficacy of chemo/radiotherapy and molecular targeted agents, and reverse drug resistance of cancer cells. Taken together, CHM plays a vital role in the prevention and treatment of tumor initiation, development, and progression. Moreover, it is a promising strategy to develop low-toxic and effective antitumor agents from CHMs based on the regulation ROS. Notably, the majority of current mechanistic researches are based on the reductionist approach, which may not adequately clarify the efficacy of herbal medicines, especially for the traditional Chinese compound formulas, the most common way used in the clinic. Therefore, a systematic biological method may be more appropriate and efficient for the development of effective therapies; additionally, more well-designed clinical trials and transformational experimental studies are also vitally needed to confirm the efficacy of CHMs in humans.

Conflicts of Interest

All the authors declare that there are no potential conflicts of interest regarding this article.

Authors' Contributions

Qiaohong Qian and Wanqing Chen, the first two authors, equally contribute to this work.


This work was supported by the outstanding youth project of Shanghai Municipal Health Committee (2017YQ049), Shanghai Natural Science Foundation (16ZR1404000), and the Natural Science Foundation of China (81603590 and 81673947).


[1] O. Vafa, M. Wade, S. Kern et al., "c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability," Molecular Cell, vol. 9, no. 5, pp. 1031-1044, 2002.

[2] G. Y. Liou and P. Storz, "Reactive oxygen species in cancer," Free Radical Research, vol. 44, no. 5, pp. 479-496, 2010.

[3] T. Ozben, "Antioxidant supplementation on cancer risk and during cancer therapy: an update," Current Topics in Medicinal Chemistry, vol. 15, no. 2, pp. 170-178, 2015.

[4] G. Bjelakovic, D. Nikolova, L. L. Gluud, R. G. Simonetti, and C. Gluud, "Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis," JAMA, vol. 297, no. 8, pp. 842-857, 2007.

[5] G. M. DeNicola, F. A. Karreth, T. J. Humpton et al., "Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis," Nature, vol. 475, no. 7354, pp. 106-109, 2011.

[6] E. Piskounova, M. Agathocleous, M. M. Murphy et al., "Oxidative stress inhibits distant metastasis by human melanoma cells," Nature, vol. 527, no. 7577, pp. 186-191, 2015.

[7] M. Carocho and I. C. F. R. Ferreira, "A review on antioxidants, prooxidants and related controversy: natural and synthetic compounds, screening and analysis methodologies and future perspectives," Food and Chemical Toxicology, vol. 51, pp. 15-25, 2013.

[8] M. Schieber and N. S. Chandel, "ROS function in redox signaling and oxidative stress," Current Biology, vol. 24, no. 10, pp. R453-R462, 2014.

[9] M. Li-Weber, "Targeting apoptosis pathways in cancer by Chinese medicine," Cancer Letters, vol. 332, no. 2, pp. 304-312, 2013.

[10] H. Xu, X. Zhao, X. Liu et al., "Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway," Drug Design, Development and Therapy, vol. 9, pp. 2735-2744, 2015.

[11] F. Qi, A. Li, Y. Inagaki et al., "Chinese herbal medicines as adjuvant treatment during chemo- or radio-therapy for cancer," Bioscience Trends, vol. 4, no. 6, pp. 297-307, 2010.

[12] Z. Wang, F. Qi, Y. Cui et al., "An update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics," Bioscience Trends, vol. 12, no. 3, pp. 220-239, 2018.

[13] M. J. Akhtar, M. Ahamed, and H. A. Alhadlaq, "Therapeutic targets in the selective killing of cancer cells by nanomaterials," Clinica Chimica Acta, vol. 469, pp. 53-62, 2017.

[14] D. E. Handy and J. Loscalzo, "Redox regulation of mitochondrial function," Antioxidants & Redox Signaling, vol. 16, no. 11, pp. 1323-1367, 2012.

[15] D. B. Zorov, M. Juhaszova, and S. J. Sollott, "Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release," Physiological Reviews, vol. 94, no. 3, pp. 909-950, 2014.

[16] 1.1. C. Chio and D. A. Tuveson, "ROS in cancer: the burning question," Trends in Molecular Medicine, vol. 23, no. 5, pp. 411-429, 2017.

[17] L. Tong, C. C. Chuang, S. Wu, and L. Zuo, "Reactive oxygen species in redox cancer therapy," Cancer Letters, vol. 367, no. 1, pp. 18-25, 2015.

[18] J. N. Moloney and T. G. Cotter, "ROS signalling in the biology of cancer," Seminars in Cell & Developmental Biology, vol. 80, pp. 50-64, 2018.

[19] P. Inarrea, H. Moini, D. Rettori et al., "Redox activation of mitochondrial intermembrane space Cu,Zn-superoxide dismutase," Biochemical Journal, vol. 387, no. 1, pp. 203-209, 2005.

[20] S. Galadari, A. Rahman, S. Pallichankandy, and F. Thayyullathil, "Reactive oxygen species and cancer paradox: to promote or to suppress?," Free Radical Biology and Medicine, vol. 104, pp. 144-164, 2017.

[21] N. Couto, J. Wood, and J. Barber, "The role of glutathione reductase and related enzymes on cellular redox homoeostasis network," Free Radical Biology and Medicine, vol. 95, pp. 27-42, 2016.

[22] M. Kobayashi and M. Yamamoto, "Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation," Antioxidants & Redox Signaling, vol. 7, no. 3-4, pp. 385-394, 2005.

[23] R. A. Cairns, I. S. Harris, and T. W. Mak, "Regulation of cancer cell metabolism," Nature Reviews Cancer, vol. 11, no. 2, pp. 85-95, 2011.

[24] Y. M. W. Janssen-Heininger, B. T. Mossman, N. H. Heintz et al., "Redox-based regulation of signal transduction: principles, pitfalls, and promises," Free Radical Biology and Medicine, vol. 45, no. 1, pp. 1-17, 2008.

[25] A. V. Bazhin, P. P. Philippov, and S. Karakhanova, "Reactive oxygen species in cancer biology and anticancer therapy," Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 4197815, 2 pages, 2016.

[26] C. Gorrini, I. S. Harris, and T. W. Mak, "Modulation of oxidative stress as an anticancer strategy," Nature Reviews Drug Discovery, vol. 12, no. 12, pp. 931-947, 2013.

[27] M. Tafani, L. Sansone, F. Limana et al., "The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in cancer initiation and progression," Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 3907147, 18 pages, 2016.

[28] A. Maciag, G. Sithanandam, and L. M. Anderson, "Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells," Carcinogenesis, vol. 25, no. 11, pp. 2231-2237, 2004.

[29] M. Ogrunc, R. di Micco, M. Liontos et al., "Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation," Cell Death & Differentiation, vol. 21, no. 6, pp. 998-1012, 2014.

[30] A. Chatterjee, E. Mambo, and D. Sidransky, "Mitochondrial DNA mutations in human cancer," Oncogene, vol. 25, no. 34, pp. 4663-4674, 2006.

[31] S. S. Sabharwal and P. T. Schumacker, "Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?," Nature Reviews Cancer, vol. 14, no. 11, pp. 709-721, 2014.

[32] V. Helfinger and K. Schroder, "Redox control in cancer development and progression," Molecular Aspects of Medicine, vol. 63, pp. 88-98, 2018.

[33] D. Hanahan and R. A. Weinberg, "Hallmarks of cancer: the next generation," Cell, vol. 144, no. 5, pp. 646-674, 2011.

[34] S. R. Lee, K. S. Yang, J. Kwon, C. Lee, W. Jeong, and S. G. Rhee, "Reversible inactivation of the tumor suppressor PTEN by [H.sub.2][O.sub.2]," Journal of Biological Chemistry, vol. 277, no. 23, pp. 2023326-20342, 2002.

[35] A. Salmeen, J. N. Andersen, M. P. Myers et al., "Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate," Nature, vol. 423, no. 6941, pp. 769-773, 2003.

[36] Y. Son, Y. K. Cheong, N. H. Kim, H. T. Chung, D. G. Kang, and H. O. Pae, "Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways?," Journal of Signal Transduction, vol. 2011, Article ID 792639, 6 pages, 2011.

[37] J. E. Klaunig, Z. Wang, X. Pu, and S. Zhou, "Oxidative stress and oxidative damage in chemical carcinogenesis," Toxicology and Applied Pharmacology, vol. 254, no. 2, pp. 86-99, 2011.

[38] T. Pralhad, S. Madhusudan, and K. Rajendrakumar, "Concept, mechanisms and therapeutics of angiogenesis in cancer and other diseases," Journal of Pharmacy and Pharmacology, vol. 55, no. 8, pp. 1045-1053, 2003.

[39] H. Peshavariya, G. J. Dusting, F. Jiang et al., "NADPH oxidase isoform selective regulation of endothelial cell proliferation and survival," Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 380, no. 2, pp. 193-204, 2009.

[40] E. Monaghan-Benson and K. Burridge, "The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species," Journal of Biological Chemistry, vol. 284, no. 38, pp. 25602-25611, 2009.

[41] M. Yamaoka-Tojo, T. Tojo, H. W. Kim et al., "IQGAP1 mediates VE-cadherin-based cell-cell contacts and VEGF signaling at adherence junctions linked to angiogenesis," Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 9, pp. 1991-1997, 2006.

[42] A. B. Hwang and S. J. Lee, "Regulation of life span by mitochondrial respiration: the HIF-1 and ROS connection," Aging, vol. 3, no. 3, pp. 304-310, 2011.

[43] Z. A. Sibenaller, J. L. Welsh, C. du et al., "Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1[alpha] in pancreatic cancer," Free Radical Biology and Medicine, vol. 69, pp. 357-366, 2014.

[44] S. Kaewpila, S. Venkataraman, G. R. Buettner, and L. W. Oberley, "Manganese superoxide dismutase modulates hypoxia-inducible factor-1[alpha] induction via superoxide," Cancer Research, vol. 68, no. 8, pp. 2781-2788, 2008.

[45] A. C. Chiang and J. Massague, "Molecular basis of metastasis," New England Journal of Medicine, vol. 359, no. 26, pp. 2814-2823, 2008.

[46] B. Diaz, G. Shani, I. Pass, D. Anderson, M. Quintavalle, and S. A. Courtneidge, "Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation," Science Signaling, vol. 2, no. 88, article ra53,2009.

[47] E. Giannoni, T. Fiaschi, G. Ramponi, and P. Chiarugi, "Redox regulation of anoikis resistance of metastatic prostate cancer cells: key role for Src and EGFR-mediated pro-survival signals," Oncogene, vol. 28, no. 20, pp. 2074-2086, 2009.

[48] S. Basuroy, M. Dunagan, P. Sheth, A. Seth, and R. K. Rao, "Hydrogen peroxide activates focal adhesion kinase and c-Src by a phosphatidylinositol 3 kinase-dependent mechanism and promotes cell migration in Caco-2 cell monolayers," American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 299, no. 1, pp. G186-G195, 2010.

[49] S. A. Brooks, H. J. Lomax-Browne, T. M. Carter, C. E. Kinch, and D. M. S. Hall, "Molecular interactions in cancer cell metastasis," Acta Histochemica, vol. 112, no. 1, pp. 3-25, 2010.

[50] L. Tochhawng, S. Deng, S. Pervaiz, and C. T. Yap, "Redox regulation of cancer cell migration and invasion," Mitochondrion, vol. 13, no. 3, pp. 246-253, 2013.

[51] N. Tobar, V. Villar, and J. F. Santibanez, "ROS-NF[kappa]B mediates TGF-[beta]1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion," Molecular and Cellular Biochemistry, vol. 340, no. 1-2, pp. 195-202, 2010.

[52] S. Cannito, E. Novo, A. Compagnone et al., "Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells," Carcinogenesis, vol. 29, no. 12, pp. 2267-2278, 2008.

[53] S. Lamouille, J. Xu, and R. Derynck, "Molecular mechanisms of epithelial-mesenchymal transition," Nature Reviews Molecular Cell Biology, vol. 15, no. 3, pp. 178-196, 2014.

[54] H. Sui, L. Zhu, W. Deng, and Q. Li, "Epithelial-mesenchymal transition and drug resistance: role, molecular mechanisms, and therapeutic strategies," Oncology Research and Treatment, vol. 37, no. 10, pp. 584-589, 2014.

[55] M. Redza-Dutordoir and D. A. Averill-Bates, "Activation of apoptosis signalling pathways by reactive oxygen species," Biochimica et Biophysica Acta (BBA)--Molecular Cell Research, vol. 1863, no. 12, pp. 2977-2992, 2016.

[56] Z. Zou, H. Chang, H. Li, and S. Wang, "Induction of reactive oxygen species: an emerging approach for cancer therapy," Apoptosis, vol. 22, no. 11, pp. 1321-1335, 2017.

[57] L. Wang, N. Azad, L. Kongkaneramit et al., "The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation," The Journal of Immunology, vol. 180, no. 5, pp. 3072-3080, 2008.

[58] P. J. Nadeau, S. J. Charette, and J. Landry, "REDOX reaction at ASK1-Cys250 is essential for activation of JNK and induction of apoptosis," Molecular Biology of the Cell, vol. 20, no. 16, pp. 3628-3637, 2009.

[59] S. W. Ryter, H. P. Kim, A. Hoetzel et al., "Mechanisms of cell death in oxidative stress," Antioxidants & Redox Signaling, vol. 9, no. 1, pp. 49-89, 2007.

[60] S. A. Susin, H. K. Lorenzo, N. Zamzami et al., "Molecular characterization of mitochondrial apoptosis-inducing factor," Nature, vol. 397, no. 6718, pp. 441-446, 1999.

[61] S. Luanpitpong, P. Chanvorachote, C. Stehlik et al., "Regulation of apoptosis by Bcl-2 cysteine oxidation in human lung epithelial cells," Molecular Biology of the Cell, vol. 24, no. 6, pp. 858-869, 2013.

[62] M. O. Hengartner, "The biochemistry of apoptosis," Nature, vol. 407, no. 6805, pp. 770-776, 2000.

[63] J. D. Malhotra, H. Miao, K. Zhang et al., "Antioxidants reduce endoplasmic reticulum stress and improve protein secretion," Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 47, pp. 18525-18530, 2008.

[64] H. M. A. Zeeshan, G. H. Lee, H. R. Kim, and H. J. Chae, "Endoplasmic reticulum stress and associated ROS," International Journal of Molecular Sciences, vol. 17, no. 3, p. 327, 2016.

[65] S. Orrenius, V. Gogvadze, and B. Zhivotovsky, "Calcium and mitochondria in the regulation of cell death," Biochemical and Biophysical Research Communications, vol. 460, no. 1, pp. 72-81, 2015.

[66] A. Delaunay-Moisan and C. Appenzeller-Herzog, "The antioxidant machinery of the endoplasmic reticulum: protection and signaling," Free Radical Biology and Medicine, vol. 83, pp. 341-351,2015.

[67] C. He and D. J. Klionsky, "Regulation mechanisms and signaling pathways of autophagy," Annual Review of Genetics, vol. 43, no. 1, pp. 67-93, 2009.

[68] L. Li, G. Ishdorj, and S. B. Gibson, "Reactive oxygen species regulation of autophagy in cancer: implications for cancer treatment," Free Radical Biology and Medicine, vol. 53, no. 7, pp. 1399-1410, 2012.

[69] Y. Chen, E. McMillan-Ward, J. Kong, S. J. Israels, and S. B. Gibson, "Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells," Cell Death & Differentiation, vol. 15, no. 1, pp. 171-182, 2008.

[70] F. Thayyullathil, A. Rahman, S. Pallichankandy, M. Patel, and S. Galadari, "ROS-dependent prostate apoptosis response-4 (Par-4) up-regulation and ceramide generation are the prime signaling events associated with curcumin-induced autophagic cell death in human malignant glioma," FEBS Open Bio, vol. 4, no. 1, pp. 763-776, 2014.

[71] Y. Zhao, T. Qu, P. Wang et al., "Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy," Apoptosis, vol. 21, no. 5, pp. 517-531, 2016.

[72] R. Scherz-Shouval, E. Shvets, E. Fass, H. Shorer, L. Gil, and Z. Elazar, "Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4," The EMBO Journal, vol. 26, no. 7, pp. 1749-1760, 2007.

[73] Z. Guo, S. Kozlov, M. F. Lavin, M. D. Person, and T. T. Paull, "ATM activation by oxidative stress," Science, vol. 330, no. 6003, pp. 517-521, 2010.

[74] L. Li, Y. Chen, and S. B. Gibson, "Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation," Cellular Signalling, vol. 25, no. 1, pp. 50-65, 2013.

[75] D. Egan, J. Kim, R. J. Shaw, and K. L. Guan, "The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR," Autophagy, vol. 7, no. 6, pp. 643-644, 2011.

[76] Y. J. Byun, S. K. Kim, Y. M. Kim, G. T. Chae, S. W. Jeong, and S. B. Lee, "Hydrogen peroxide induces autophagic cell death in C6 glioma cells via BNIP3-mediated suppression of the mTOR pathway," Neuroscience Letters, vol. 461, no. 2, pp. 131-135, 2009.

[77] G. Bellot, R. Garcia-Medina, P. Gounon et al., "Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains," Molecular and Cellular Biology, vol. 29, no. 10, pp. 2570-2581, 2009.

[78] M. Djavaheri-Mergny, M. Amelotti, J. Mathieu et al., "NF-[kappa]B activation represses tumor necrosis factor-[alpha]-induced autophagy," Journal of Biological Chemistry, vol. 281, no. 41, pp. 30373-30382, 2006.

[79] L. Poillet-Perez, G. Despouy, R. Delage-Mourroux, and M. Boyer-Guittaut, "Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy," Redox Biology, vol. 4, pp. 184-192, 2015.

[80] M. Komatsu, H. Kurokawa, S. Waguri et al., "The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1," Nature Cell Biology, vol. 12, no. 3, pp. 213-223, 2010.

[81] N. F. Villeneuve, A. Lau, and D. D. Zhang, "Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases," Antioxidants & Redox Signaling, vol. 13, no. 11, pp. 1699-1712, 2010.

[82] S. J. Dixon, K. M. Lemberg, M. R. Lamprecht et al., "Ferroptosis: an iron-dependent form of nonapoptotic cell death," Cell, vol. 149, no. 5, pp. 1060-1072, 2012.

[83] W. S. Yang and B. R. Stockwell, "Ferroptosis: death by lipid peroxidation," Trends in Cell Biology, vol. 26, no. 3, pp. 165-176, 2016.

[84] B. R. Stockwell, J. P. Friedmann Angeli, H. Bayir et al., "Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease," Cell, vol. 171, no. 2, pp. 273-285, 2017.

[85] R. Skouta, S. J. Dixon, J. Wang et al., "Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models," Journal of the American Chemical Society, vol. 136, no. 12, pp. 4551-4556, 2014.

[86] W. S. Yang, R. SriRamaratnam, M. E. Welsch et al., "Regulation of ferroptotic cancer cell death by GPX4," Cell, vol. 156, no. 1-2, pp. 317-331, 2014.

[87] O. Zilka, R. Shah, B. Li et al., "On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death," ACS Central Science, vol. 3, no. 3, pp. 232-243, 2017.

[88] Z. Cheng and Y. Li, "What is responsible for the initiating chemistry of iron-mediated lipid peroxidation: an update," Chemical Reviews, vol. 107, no. 3, pp. 748-766, 2007.

[89] Y. Xie, W. Hou, X. Song et al., "Ferroptosis: process and function," Cell Death & Differentiation, vol. 23, no. 3, pp. 369-379, 2016.

[90] M. Gao, P. Monian, N. Quadri, R. Ramasamy, and X. Jiang, "Glutaminolysis and transferrin regulate ferroptosis," Molecular Cell, vol. 59, no. 2, pp. 298-308, 2015.

[91] X. Sun, Z. Ou, M. Xie et al., "HSPB1 as a novel regulator of ferroptotic cancer cell death," Oncogene, vol. 34, no. 45, pp. 5617-5625, 2015.

[92] L. Jiang, N. Kon, T. Li et al., "Ferroptosis as a p53-mediated activity during tumour suppression," Nature, vol. 520, no. 7545, pp. 57-62, 2015.

[93] L. Jiang, J. H. Hickman, S. J. Wang, and W. Gu, "Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses," Cell Cycle, vol. 14, no. 18, pp. 2881-2885, 2015.

[94] W. L. Hsiao and L. Liu, "The role of traditional Chinese herbal medicines in cancer therapy--from TCM theory to mechanistic insights," Planta Medica, vol. 76, no. 11, pp. 1118-1131,2010.

[95] F. L. Buchner, H. B. Bueno-de-Mesquita, J. Linseisen et al., "Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)," Cancer Causes & Control, vol. 21, no. 3, pp. 357-371, 2010.

[96] M. Shareck, M. C. Rousseau, A. Koushik, J. Siemiatycki, and M. E. Parent, "Inverse association between dietary intake of selected carotenoids and vitamin C and risk of lung cancer," Frontiers in Oncology, vol. 7, p. 23, 2017.

[97] R. Jiao, Y. Liu, H. Gao, J. Xiao, and K. F. So, "The anti-oxidant and antitumor properties of plant polysaccharides," The American Journal of Chinese Medicine, vol. 44, no. 3, pp. 463-488, 2016.

[98] P. Pratheeshkumar, Y. O. Son, S. P. Divya et al., "Quercetin inhibits Cr(VI)-induced malignant cell transformation by targeting miR-21-PDCD4 signaling pathway," Oncotarget, vol. 8, no. 32, pp. 52118-52131, 2017.

[99] Y. Li, Y. Hu, S. Shi, and L. Jiang, "Evaluation of antioxidant and immuno-enhancing activities of purslane polysaccharides in gastric cancer rats," International Journal of Biological Macromolecules, vol. 68, pp. 113-116, 2014.

[100] J. Bao, R. Ding, L. Zou et al., "Forsythiae Fructus inhibits B16 melanoma growth involving MAPKs/Nrf2/HO-1 mediated anti-oxidation and anti-inflammation," The American Journal of Chinese Medicine, vol. 44, no. 05, pp. 1043-1061, 2016.

[101] M. Yuan, W. Meng, W. Liao, and S. Lian, "Andrographolide antagonizes TNF-[alpha]-induced IL-8 via inhibition of NADPH oxidase/ROS/NF-[kappa]B and Src/MAPKs/AP-1 axis in human colorectal cancer HCT116 cells," Journal of Agricultural and Food Chemistry, vol. 66, no. 20, pp. 5139-5148, 2018.

[102] X. Zhang, E. D. Yeung, J. Wang et al., "Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cells," Clinical and Experimental Pharmacology and Physiology, vol. 37, no. 8, pp. 841-847, 2010.

[103] G. T. Kwon, H. J. Cho, W. Y. Chung, K. K. Park, A. Moon, and J. H. Y. Park, "Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling," The Journal of Nutritional Biochemistry, vol. 20, no. 9, pp. 663-676, 2009.

[104] B. Yan, L. Cheng, Z. Jiang et al., "Resveratrol inhibits ROS-promoted activation and glycolysis of pancreatic stellate cells via suppression of miR-21," Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 1346958,15 pages, 2018.

[105] H. R. Teppo, Y. Soini, and P. Karihtala, "Reactive oxygen species-mediated mechanisms of action of targeted cancer therapy," Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 1485283, 11 pages, 2017.

[106] D. Trachootham, J. Alexandre, and P. Huang, "Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?," Nature Reviews Drug Discovery, vol. 8, no. 7, pp. 579-591, 2009.

[107] B. Li, D. S. Kim, R. K. Yadav, H. R. Kim, and H. J. Chae, "Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells," International Journal of Molecular Medicine, vol. 36, no. 1, pp. 53-64, 2015.

[108] A. Yanaka, "Sulforaphane enhances protection and repair of gastric mucosa against oxidative stress in vitro, and demonstrates anti-inflammatory effects on Helicobacter pylori-infected gastric mucosae in mice and human subjects," Current Pharmaceutical Design, vol. 17, no. 16, pp. 1532-1540, 2011.

[109] L. Li, J. Ni, M. Li et al., "Ginsenoside Rg3 micelles mitigate doxorubicin-induced cardiotoxicity and enhance its anticancer efficacy," Drug Delivery, vol. 24, no. 1, pp. 1617-1630, 2017.

[110] B. Ahmmed, S. Kampo, M. Khan et al., "Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-[kappa]B- and HIF-1[alpha]-mediated downregulation of PTX3," Journal of Cellular Physiology, vol. 234, no. 7, pp. 10680-10697, 2019.

[111] Y. Gao, S. Chu, Q. Shao et al., "Antioxidant activities of ginsenoside Rg1 against cisplatin-induced hepatic injury through Nrf2 signaling pathway in mice," Free Radical Research, vol. 51, no. 1, pp. 1-13, 2017.

[112] J. Jin, M. Li, Z. Zhao et al., "Protective effect of Wuzhi tablet (Schisandra sphenanthera extract) against cisplatin-induced nephrotoxicity via Nrf2-mediated defense response," Phytomedicine, vol. 22, no. 5, pp. 528-535, 2015.

[113] W. N. Yu, L. F. Sun, and H. Yang, "Inhibitory effects of astragaloside IV on bleomycin-induced pulmonary fibrosis in rats via attenuation of oxidative stress and inflammation," Inflammation, vol. 39, no. 5, pp. 1835-1841, 2016.

[114] J. Yun, E. Mullarky, C. Lu et al., "Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH," Science, vol. 350, no. 6266, pp. 1391-1396, 2015.

[115] C. Sun, H. Zhang, X. F. Ma et al., "Isoliquiritigenin enhances radiosensitivity of HepG2 cells via disturbance of redox status," Cell Biochemistry and Biophysics, vol. 65, no. 3, pp. 433-444, 2013.

[116] J. D. Lambert and R. J. Elias, "The antioxidant and prooxidant activities of green tea polyphenols: a role in cancer prevention," Archives of Biochemistry and Biophysics, vol. 501, no. 1, pp. 65-72, 2010.

[117] G. Galati, A. Lin, A. M. Sultan, and P. J. O'Brien, "Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins," Free Radical Biology and Medicine, vol. 40, no. 4, pp. 570-580, 2006.

[118] W. Shi, L. Li, Y. Ding et al., "The critical role of epigallocatechin gallate in regulating mitochondrial metabolism," Future Medicinal Chemistry, vol. 10, no. 7, pp. 795-809, 2018.

[119] A. Glasauer and N. S. Chandel, "Targeting antioxidants for cancer therapy," Biochemical Pharmacology, vol. 92, no. 1, pp. 90-101, 2014.

[120] S. Baumann, S. C. Fas, M. Giaisi et al., "Wogonin preferentially kills malignant lymphocytes and suppresses T-cell tumor growth by inducing PLCy1- and [Ca.sup.2+]-dependent apoptosis," Blood, vol. 111, no. 4, pp. 2354-2363, 2008.

[121] L. Yang, Q. Wang, D. Li et al., "Wogonin enhances antitumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated downregulation of cFLIPL and IAP proteins," Apoptosis, vol. 18, no. 5, pp. 618-626, 2013.

[122] Y. Yang, Y. Zhang, L. Wang, and S. Lee, "Levistolide A induces apoptosis via ROS-mediated ER stress pathway in colon cancer cells," Cellular Physiology and Biochemistry, vol. 42, no. 3, pp. 929-938, 2017.

[123] F. Chen, T. Wang, J. Wang, Z. Q. Wang, and M. Qian, "Levistolide A overcomes P-glycoprotein-mediated drug resistance in human breast carcinoma cells," Acta Pharmacologica Sinica, vol. 29, no. 4, pp. 458-464, 2008.

[124] J. Yang, Z. Fang, J. Wu et al., "Construction and application of a lung cancer stem cell model: antitumor drug screening and molecular mechanism of the inhibitory effects of sanguinarine," Tumor Biology, vol. 37, no. 10, pp. 13871-13883, 2016.

[125] S. Pallichankandy, A. Rahman, F. Thayyullathil, and S. Galadari, "ROS-dependent activation of autophagy is a critical mechanism for the induction of anti-glioma effect of sanguinarine," Free Radical Biology and Medicine, vol. 89, pp. 708-720, 2015.

[126] E. L. H. Leung, X. X. Fan, M. P. Wong et al., "Targeting tyrosine kinase inhibitor-resistant non-small cell lung cancer by inducing epidermal growth factor receptor degradation via methionine 790 oxidation," Antioxidants & Redox Signaling, vol. 24, no. 5, pp. 263-279, 2016.

[127] A. Hamacher-Brady, H. A. Stein, S. Turschner et al., "Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production," Journal of Biological Chemistry, vol. 286, no. 8, pp. 6587-6601,2011.

[128] N. Eling, L. Reuter, J. Hazin, A. Hamacher-Brady, and N. R. Brady, "Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells," Oncoscience, vol. 2, no. 5, pp. 517-532, 2015.

[129] G. Q. Chen, F. A. Benthani, J. Wu, D. Liang, Z. X. Bian, and X. Jiang, "Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis," Cell Death & Differentiation, 2019.

[130] A. J. Leon-Gonzalez, C. Auger, and V. B. Schini-Kerth, "Prooxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy," Biochemical Pharmacology, vol. 98, no. 3, pp. 371-380, 2015.

[131] Y. R. Kim, J. E. Oh, M. S. Kim et al., "Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin," The Journal of Pathology, vol. 220, no. 4, pp. 446-451, 2010.

[132] M. L. Teoh-Fitzgerald, M. P. Fitzgerald, W. Zhong, R. W. Askeland, and F. E. Domann, "Epigenetic reprogramming governs EcSOD expression during human mammary epithelial cell differentiation, tumorigenesis and metastasis," Oncogene, vol. 33, no. 3, pp. 358-368, 2014.

[133] P. C. Hart, M. Mao, A. L. P. de Abreu et al., "MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer," Nature Communications, vol. 6, no. 1, article 6053, 2015.

[134] L. Raj, T. Ide, A. U. Gurkar et al., "Selective killing of cancer cells by a small molecule targeting the stress response to ROS," Nature, vol. 475, no. 7355, pp. 231-234, 2011.

[135] J. L. Roh, E. H. Kim, J. Y. Park, J. W. Kim, M. Kwon, and B. H. Lee, "Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer," Oncotarget, vol. 5, no. 19, pp. 9227-9238, 2014.

[136] W. Harshbarger, S. Gondi, S. B. Ficarro et al., "Structural and biochemical analyses reveal the mechanism of glutathione S-transferase Pi 1 inhibition by the anti-cancer compound piperlongumine," Journal of Biological Chemistry, vol. 292, no. 1, pp. 112-120, 2017.

[137] X. Sun, W. Wang, J. Chen et al., "The natural diterpenoid isoforretin A inhibits thioredoxin-1 and triggers potent ROS-mediated antitumor effects," Cancer Research, vol. 77, no. 4, pp. 926-936, 2017.

[138] D. Duan, B. Zhang, J. Yao, Y. Liu, and J. Fang, "Shikonin targets cytosolic thioredoxin reductase to induce ROS-mediated apoptosis in human promyelocytic leukemia HL-60 cells," Free Radical Biology and Medicine, vol. 70, pp. 182-193, 2014.

[139] X. Li, X. X. Fan, Z. B. Jiang et al., "Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway," Pharmacological Research, vol. 115, pp. 45-55, 2017.

[140] D. Duan, J. Zhang, J. Yao, Y. Liu, and J. Fang, "Targeting thioredoxin reductase by parthenolide contributes to inducing apoptosis of HeLa cells," Journal of Biological Chemistry, vol. 291, no. 19, pp. 10021-10031, 2016.

[141] B. Harder, W. Tian, J. J. La Clair et al., "Brusatol overcomes chemoresistance through inhibition of protein translation," Molecular Carcinogenesis, vol. 56, no. 5, pp. 1493-1500,2017.

[142] D. Ren, N. F. Villeneuve, T. Jiang et al., "Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism," Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 4, pp. 1433-1438, 2011.

[143] M. Wang, G. Shi, C. Bian et al., "UVA irradiation enhances brusatol-mediated inhibition of melanoma growth by downregulation of the Nrf2-mediated antioxidant response," Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 9742154, 15 pages, 2018.

[144] L. Zhang, J. Li, L. Zong et al., "Reactive Oxygen Species and Targeted Therapy for Pancreatic Cancer," Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 1616781, 9 pages, 2016.

[145] G. Bjelakovic, D. Nikolova, and C. Gluud, "Antioxidant supplements to prevent mortality," JAMA, vol. 310, no. 11, pp. 1178-1179, 2013.

[146] K. Le Gal, M. X. Ibrahim, C. Wiel et al., "Antioxidants can increase melanoma metastasis in mice," Science Translational Medicine, vol. 7, no. 308, p. 308re8, 2015.

[147] M. Filippova, V. Filippov, V. M. Williams et al., "Cellular levels of oxidative stress affect the response of cervical cancer cells to chemotherapeutic agents," BioMed Research International, vol. 2014, Article ID 574659, 14 pages, 2014.

[148] M. Fukui, N. Yamabe, and B. T. Zhu, "Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells in vitro and in vivo," European Journal of Cancer, vol. 46, no. 10, pp. 1882-1891, 2010.

[149] C. Martin-Cordero, A. Jose Leon-Gonzalez, J. Manuel Calderon-Montano, E. Burgos-Moron, and M. Lopez-Lazaro, "Pro-oxidant natural products as anticancer agents," Current Drug Targets, vol. 13, no. 8, pp. 1006-1028, 2012.

[150] Y. Yang, Y. Hu, and H. Wang, "Targeting antitumor immune response for enhancing the efficacy of photodynamic therapy of cancer: recent advances and future perspectives," Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 5274084, 11 pages, 2016.

[151] M. Lopez-Lazaro, "Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent," Molecular Nutrition & Food Research, vol. 52, Supplement 1, pp. S103-S127, 2008.

[152] Y. Wang, S. H. Guo, X. J. Shang et al., "Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response," Acta Pharmacologica Sinica, vol. 39, no. 2, pp. 311-327, 2018.

[153] W. Yan, Y. Xu, Y. Yuan et al., "Renoprotective mechanisms of astragaloside IV in cisplatin-induced acute kidney injury," Free Radical Research, vol. 51, no. 7-8, pp. 669-683, 2017.

[154] N. Miyoshi, S. Takabayashi, T. Osawa, and Y. Nakamura, "Benzyl isothiocyanate inhibits excessive superoxide generation in inflammatory leukocytes: implication for prevention against inflammation-related carcinogenesis," Carcinogenesis, vol. 25, no. 4, pp. 567-575, 2004.

[155] W. Chen, X. Li, L. Q. Jia et al., "Neuroprotective activities of catalpol against CaMKII-dependent apoptosis induced by LPS in PC12 cells," British Journal of Pharmacology, vol. 169, no. 5, pp. 1140-1152, 2013.

[156] S. H. Hashemi-Shahri, A. Golshan, S. A. Mohajeri et al., "ROS-scavenging and anti-tyrosinase properties of crocetin on B16F10 murine melanoma cells," Anti-Cancer Agents in Medicinal Chemistry, vol. 18, no. 7, pp. 1064-1069, 2018.

[157] A. Jain, A. Samykutty, C. Jackson et al., "Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets," Cancer Letters, vol. 365, no. 1, pp. 122-131,2015.

[158] L. Zhao, X. Tao, Y. Qi, L. Xu, L. Yin, and J. Peng, "Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress," Redox Biology, vol. 16, pp. 189-198, 2018.

[159] H. Lv, Q. Liu, J. Zhou, G. Tan, X. Deng, and X. Ci, "Daphnetin-mediated Nrf2 antioxidant signaling pathways ameliorate tert-butyl hydroperoxide (t-BHP)-induced mitochondrial dysfunction and cell death," Free Radical Biology and Medicine, vol. 106, pp. 38-52, 2017.

[160] K. N. M. Abdelazeem, Y. Singh, F. Lang, and M. S. Salker, "Negative effect of ellagic acid on cytosolic pH regulation and glycolytic flux in human endometrial cancer cells," Cellular Physiology and Biochemistry, vol. 41, no. 6, pp. 2374-2382, 2017.

[161] M. C. Lin and M. C. Yin, "Preventive effects of ellagic acid against doxorubicin-induced cardio-toxicity in mice," Cardiovascular Toxicology, vol. 13, no. 3, pp. 185-193, 2013.

[162] H. Lou, X. Jing, D. Ren, X. Wei, and X. Zhang, "Eriodictyol protects against [H.sub.2][O.sub.2]-induced neuron-like PC12 cell death through activation of Nrf2/ARE signaling pathway," Neurochemistry International, vol. 61, no. 2, pp. 251-257, 2012.

[163] V. Borse, R. F. H. Al Aameri, K. Sheehan et al., "Epigallocatechin-3-gallate, a prototypic chemopreventative agent for protection against cisplatin-based ototoxicity," Cell Death & Disease, vol. 8, no. 7, article e2921, 2017.

[164] S. Choudhary, S. Sood, R. L. Donnell, and H. C. R. Wang, "Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine," Carcinogenesis, vol. 33, no. 4, pp. 876-885, 2012.

[165] A. Patricia Moreno-Londono, C. Bello-Alvarez, and J. Pedraza-Chaverri, "Isoliquiritigenin pretreatment attenuates cisplatin induced proximal tubular cells (LLC-PK1) death and enhances the toxicity induced by this drug in bladder cancer T24 cell line," Food and Chemical Toxicology, vol. 109, Part 1, pp. 143-154, 2017.

[166] P. Pratheeshkumar, Y. O. Son, S. P. Divya et al., "Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways," Toxicology and Applied Pharmacology, vol. 281, no. 2, pp. 230-241, 2014.

[167] Y. O. Son, P. Pratheeshkumar, Y. Wang, D. Kim, Z. Zhang, and X. Shi, "Protection from Cr(VI)-induced malignant cell transformation and tumorigenesis of Cr(VI)-transformed cells by luteolin through Nrf2 signaling," Toxicology and Applied Pharmacology, vol. 331, pp. 24-32, 2017.

[168] J. Gong, A. R. Munoz, D. Chan, R. Ghosh, and A. P. Kumar, "STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth," Oncotarget, vol. 5, no. 9, pp. 2529-2541, 2014.

[169] P. Mu, X. Gao, Z. J. Jia, and R. L. Zheng, "Natural antioxidant pedicularioside G inhibits angiogenesis and tumourigenesis in vitro and in vivo," Basic & Clinical Pharmacology & Toxicology, vol. 102, no. 1, pp. 30-34, 2007.

[170] C. J. Lin, C. C. Lee, Y. L. Shih et al., "Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy," Free Radical Biology and Medicine, vol. 52, no. 2, pp. 377-391, 2012.

[171] A. R. Alhoshani, M. M. Hafez, S. Husain et al., "Protective effect of rutin supplementation against cisplatin-induced nephrotoxicity in rats," BMC Nephrology, vol. 18, no. 1, p. 194, 2017.

[172] G. V. Ramalingayya, S. P. Cheruku, P. Nayak et al., "Rutin protects against neuronal damage in vitro and ameliorates doxorubicin-induced memory deficits in vivo in Wistar rats," Drug Design, Development and Therapy, vol. 11, pp. 1011-1026, 2017.

[173] X. Ma, C. Dang, H. Kang et al., "Saikosaponin-D reduces cisplatin-induced nephrotoxicity by repressing ROS mediated activation of MAPK and NF-[kappa]B signalling pathways," International Immunopharmacology, vol. 28, no. 1, pp. 399-408, 2015.

[174] Y. Wang, A. K. Mandal, Y. O. Son et al., "Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane," Toxicology and Applied Pharmacology, vol. 353, pp. 23-30, 2018.

[175] X. Gong, V. N. Ivanov, M. M. Davidson, and T. K. Hei, "Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death," Archives of Toxicology, vol. 89, no. 7, pp. 1057-1070, 2015.

[176] G. Y. Chen, Y. C. Shu, D. Y. Chuang, and Y. C. Wang, "Inflammatory and apoptotic regulatory activity of tanshinone IIA in Helicobacter pylori-infected cells," The American Journal of Chinese Medicine, vol. 44, no. 6, pp. 1187-1206, 2016.

[177] H. Z. Lee, C. J. Lin, W. H. Yang, W. C. Leung, and S. P. Chang, "Aloe-emodin induced DNA damage through generation of reactive oxygen species in human lung carcinoma cells," Cancer Letters, vol. 239, no. 1, pp. 55-63, 2006.

[178] M. L. Lin, Y. C. Lu, J. G. Chung et al., "Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway," Cancer Letters, vol. 291, no. 1, pp. 46-58, 2010.

[179] Y. Zhang, J. Soboloff, Z. Zhu, and S. A. Berger, "Inhibition of [Ca.sup.2+] influx is required for mitochondrial reactive oxygen species-induced endoplasmic reticulum [Ca.sup.2+] depletion and cell death in leukemia cells," Molecular Pharmacology, vol. 70, no. 4, pp. 1424-1434, 2006.

[180] H. T. Chang, C. T. Chou, D. H. Kuo, P. Shieh, C. R. Jan, and W. Z. Liang, "The mechanism of [Ca.sup.2+] movement in the involvement of baicalein-induced cytotoxicity in ZR-75-1 human breast cancer cells," Journal of Natural Products, vol. 78, no. 7, pp. 1624-1634, 2015.

[181] H. Taniguchi, T. Yoshida, M. Horinaka et al., "Baicalein overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance via two different cell-specific pathways in cancer cells but not in normal cells," Cancer Research, vol. 68, no. 21, pp. 8918-8927, 2008.

[182] X. X. Fan, E. L. H. Leung, Y. Xie et al., "Suppression of lipogenesis via reactive oxygen species-AMPK signaling for treating malignant and proliferative diseases," Antioxidants & Redox Signaling, vol. 28, no. 5, pp. 339-357, 2018.

[183] S. Shukla, F. Rizvi, S. Raisuddin, and P. Kakkar, "FoxO proteins' nuclear retention and BH3-only protein Bim induction evoke mitochondrial dysfunction-mediated apoptosis in berberine-treated HepG2 cells," Free Radical Biology and Medicine, vol. 76, pp. 185-199, 2014.

[184] Y. Li, X. Tian, X. Liu, and P. Gong, "Bufalin inhibits human breast cancer tumorigenesis by inducing cell death through the ROS-mediated RIP1/RIP3/PARP-1 pathways," Carcinogenesis, vol. 39, no. 5, pp. 700-707, 2018.

[185] C. M. Xie, W. Y. Chan, S. Yu, J. Zhao, and C. H. K. Cheng, "Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygen species generation and JNK activation," Free Radical Biology and Medicine, vol. 51, no. 7, pp. 1365-1375, 2011.

[186] H. Y. Li, J. Zhang, L. L. Sun et al., "Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study," Cell Death & Disease, vol. 6, no. 1, article e1604, 2015.

[187] Y. Xiao, J. Liu, M. Guo et al., "Synergistic combination chemotherapy using carrier-free celastrol and doxorubicin nanocrystals for overcoming drug resistance," Nanoscale, vol. 10, no. 26, pp. 12639-12649, 2018.

[188] Y. Bi, H. Li, D. Yi et al., "[beta]-catenin contributes to cordycepin-induced MGMT inhibition and reduction of temozolomide resistance in glioma cells by increasing intracellular reactive oxygen species," Cancer Letters, vol. 435, pp. 66-79, 2018.

[189] M. I. Nasser, M. Masood, W. Wei et al., "Cordycepin induces apoptosis in SGC7901 cells through mitochondrial extrinsic phosphorylation of PI3K/Akt by generating ROS," International Journal of Oncology, vol. 50, no. 3, pp. 911-919, 2017.

[190] S. Y. Lee, T. Debnath, S. K. Kim, and B. O. Lim, "Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29," Food and Chemical Toxicology, vol. 60, pp. 439-447, 2013.

[191] J. Chen, B. Chen, Z. Zou et al., "Costunolide enhances doxorubicin-induced apoptosis in prostate cancer cells via activated mitogen-activated protein kinases and generation of reactive oxygen species," Oncotarget, vol. 8, no. 64, pp. 107701-107715, 2017.

[192] Y. I. Yang, J. H. Kim, K. T. Lee, and J. H. Choi, "Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species," Gynecologic Oncology, vol. 123, no. 3, pp. 588-596, 2011.

[193] W. Zhuge, R. Chen, K. Vladimir et al., "Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer," Cancer Letters, vol. 412, pp. 46-58, 2018.

[194] Y. C. Hsu, T. Y. Huang, and M. J. Chen, "Therapeutic ROS targeting of GADD45[gamma] in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E," Cell Death & Disease, vol. 5, no. 4, article e1198, 2014.

[195] S. Jayakumar, R. S. Patwardhan, D. Pal et al., "Mitochondrial targeted curcumin exhibits anticancer effects through disruption of mitochondrial redox and modulation of TrxR2 activity," Free Radical Biology and Medicine, vol. 113, pp. 530-538, 2017.

[196] B. Kim, H. S. Kim, E. J. Jung et al., "Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells," Molecular Carcinogenesis, vol. 55, no. 5, pp. 918-928, 2016.

[197] S. Jin, Q. Y. Zhang, X. M. Kang, J. X. Wang, and W. H. Zhao, "Daidzein induces MCF-7 breast cancer cell apoptosis via the mitochondrial pathway," Annals of Oncology, vol. 21, no. 2, pp. 263-268, 2010.

[198] J. Yi, J. Yang, R. He et al., "Emodin enhances arsenic trioxide-induced apoptosis via generation of reactive oxygen species and inhibition of survival signaling," Cancer Research, vol. 64, no. 1, pp. 108-116, 2004.

[199] Y. Jing, J. Yang, Y. Wang et al., "Alteration of subcellular redox equilibrium and the consequent oxidative modification of nuclear factor [kappa]B are critical for anticancer cytotoxicity by emodin, a reactive oxygen species-producing agent," Free Radical Biology and Medicine, vol. 40, no. 12, pp. 2183-2197, 2006.

[200] T. Nakazato, K. Ito, Y. Ikeda, and M. Kizaki, "Green tea component, catechin, induces apoptosis of human malignant B cells via production of reactive oxygen species," Clinical Cancer Research, vol. 11, no. 16, pp. 6040-6049, 2005.

[201] J. Zhu, W. Yu, B. Liu et al., "Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo," Cell Death & Disease, vol. 8, no. 10, p. e3113, 2017.

[202] C. B. Yoo, K. T. Han, K. S. Cho et al., "Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukemia cells," Cancer Letters, vol. 225, no. 1, pp. 41-52, 2005.

[203] A. J. Liu, S. H. Wang, K. C. Chen et al., "Evodiamine, a plant alkaloid, induces calcium/JNK-mediated autophagy and calcium/mitochondria-mediated apoptosis in human glioblastoma cells," Chemico-Biological Interactions, vol. 205, no. 1, pp. 20-28, 2013.

[204] J. Yang, L. J. Wu, S. Tashino, S. Onodera, and T. Ikejima, "Protein tyrosine kinase pathway-derived ROS/NO productions contribute to G2/M cell cycle arrest in evodiamine-treated human cervix carcinoma HeLa cells," Free Radical Research, vol. 44, no. 7, pp. 792-802, 2010.

[205] C. Wen, L. Huang, J. Chen et al., "Gambogic acid inhibits growth, induces apoptosis, and overcomes drug resistance in human colorectal cancer cells," International Journal of Oncology, vol. 47, no. 5, pp. 1663-1671, 2015.

[206] L. H. Wang, Y. Li, S. N. Yang et al., "Gambogic acid synergistically potentiates cisplatin-induced apoptosis in nonsmall-cell lung cancer through suppressing NF-[kappa]B and MAPK/HO-1 signalling," British Journal of Cancer, vol. 110, no. 2, pp. 341-352, 2014.

[207] X. Chen, L. Pei, Z. Zhong, J. Guo, Q. Zhang, and Y. Wang, "Anti-tumor potential of ethanol extract of Curcuma phaeocaulis Valeton against breast cancer cells," Phytomedicine, vol. 18, no. 14, pp. 1238-1243, 2011.

[208] C. Liao, K. Zheng, Y. Li et al., "Gypenoside L inhibits autophagic flux and induces cell death in human esophageal cancer cells through endoplasm reticulum stress-mediated [Ca.sup.2+] release," Oncotarget, vol. 7, no. 30, pp. 47387-47402, 2016.

[209] K. Huang, Y. Chen, R. Zhang et al., "Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo," Cell Death & Disease, vol. 9, no. 2, article 157, 2018.

[210] C. J. Lin, T. L. Chen, Y. Y. Tseng et al., "Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway," Toxicol Appl Pharmacol, vol. 304, pp. 59-69,2016.

[211] P. S. Yeh, W. Wang, Y. A. Chang, C. J. Lin, J. J. Wang, and R. M. Chen, "Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration," Cancer Letters, vol. 370, no. 1, pp. 66-77, 2016.

[212] C. Fan, Y. Yang, Y. Liu et al., "Icariin displays anticancer activity against human esophageal cancer cells via regulating endoplasmic reticulum stress-mediated apoptotic signaling," Scientific Reports, vol. 6, article 21145, 2016.

[213] S. Li, P. Dong, J. Wang et al., "Icariin, a natural flavonol glycoside, induces apoptosis in human hepatoma SMMC-7721 cells via a ROS/JNK-dependent mitochondrial pathway," Cancer Letters, vol. 298, no. 2, pp. 222-230, 2010.

[214] Z. Lu, G. Zhang, Y. Zhang et al., "Isoalantolactone induces apoptosis through reactive oxygen species-dependent upregulation of death receptor 5 in human esophageal cancer cells," Toxicology and Applied Pharmacology, vol. 352, pp. 46-58, 2018.

[215] Q. Zhang, G. Cheng, H. Qiu et al., "The p53-inducible gene 3 involved in flavonoid-induced cytotoxicity through the reactive oxygen species-mediated mitochondrial apoptotic pathway in human hepatoma cells," Food & Function, vol. 6, no. 5, pp. 1518-1525, 2015.

[216] P. S. Rao, A. Satelli, M. Moridani, M. Jenkins, and U. S. Rao, "Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: involvement of cell line-specific apoptotic mechanisms," International Journal of Cancer, vol. 130, no. 11, pp. 2703-2714, 2012.

[217] Z. Xu, F. Zhang, C. Bai et al., "Sophoridine induces apoptosis and S phase arrest via ROS-dependent JNK and ERK activation in human pancreatic cancer cells," Journal of Experimental & Clinical Cancer Research, vol. 36, no. 1, article 124, 2017.

[218] H. Zhou, M. Xu, Y. Gao et al., "Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor," Molecular Cancer, vol. 13, no. 1, p. 59, 2014.

[219] P. Poornima, C. F. Weng, and V. V. Padma, "Neferine from Nelumbo nucifera induces autophagy through the inhibition of PI3K/Akt/mTOR pathway and ROS hyper generation in A549 cells," Food Chemistry, vol. 141, no. 4, pp. 3598-3605, 2013.

[220] S. Kalai Selvi, A. Vinoth, T. Varadharajan, C. F. Weng, and V. Vijaya Padma, "Neferine augments therapeutic efficacy of cisplatin through ROS- mediated non-canonical autophagy in human lung adenocarcinoma (A549 cells)," Food and Chemical Toxicology, vol. 103, pp. 28-40, 2017.

[221] C. Chang, Y. Q. Zhu, J. J. Mei, S. Q. Liu, and J. Luo, "Involvement of mitochondrial pathway in NCTD-induced cytotoxicity in human hepG2 cells," Journal of Experimental & Clinical Cancer Research, vol. 29, no. 1, p. 145, 2010.

[222] Y. Lu, Y. Sun, J. Zhu et al., "Oridonin exerts anticancer effect on osteosarcoma by activating PPAR-y and inhibiting Nrf2 pathway," Cell Death & Disease, vol. 9, no. 1, p. 15, 2018.

[223] C. Qiao, L. Wei, Q. Dai et al., "UCP2-related mitochondrial pathway participates in oroxylin A-induced apoptosis in human colon cancer cells," Journal of Cellular Physiology, vol. 230, no. 5, pp. 1054-1063, 2015.

[224] M. B. Chen, Y. Zhang, M. X. Wei et al., "Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells," Cell Signal, vol. 25, no. 10, pp. 1993-2002, 2013.

[225] B. Kumar, M. A. Iqbal, R. K. Singh, and R. N. Bamezai, "Resveratrol inhibits TIGAR to promote ROS induced apoptosis and autophagy," Biochimie, vol. 118, pp. 26-35, 2015.

[226] A. Rodriguez-Garcia, D. Hevia, J. C. Mayo et al., "Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells," Redox Biology, vol. 12, pp. 634-647, 2017.

[227] J. M. Shi, L. L. Bai, D. M. Zhang et al., "Saxifragifolin D induces the interplay between apoptosis and autophagy in breast cancer cells through ROS-dependent endoplasmic reticulum stress," Biochemical Pharmacology, vol. 85, no. 7, pp. 913-926, 2013.

[228] S. Kajimoto, N. Takanashi, T. Kajimoto et al., "Sophoranone, extracted from a traditional Chinese medicine Shan Dou Gen, induces apoptosis in human leukemia U937 cells via formation of reactive oxygen species and opening of mitochondrial permeability transition pores," International Journal of Cancer, vol. 99, no. 6, pp. 879-890, 2002.

[229] T. Liu, Z. Zhang, C. Yu et al., "Tetrandrine antagonizes acute megakaryoblastic leukaemia growth by forcing autophagy-mediated differentiation," British Journal of Pharmacology, vol. 174, no. 23, pp. 4308-4328, 2017.

[230] C. Liu, K. Gong, X. Mao, and W. Li, "Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma," International Journal of Cancer, vol. 129, no. 6, pp. 1519-1531, 2011.

[231] N. Liu, K. S. Wang, M. Qi et al., " Vitexin compound 1, a novel extraction from a Chinese herb, suppresses melanoma cell growth through DNA damage by increasing ROS levels," Journal of Experimental & Clinical Cancer Research, vol. 37, no. 1, article 269, 2018.

Qiaohong Qian, (1) Wanqing Chen, (2) Yajuan Cao, (2) Qi Cao, (1) Yajing Cui, (2) Yan Li (ID), (2) and Jianchun Wu (ID) (2)

(1) Department of Integrated Traditional Chinese and Western Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China

(2) Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China

Correspondence should be addressed to Yan Li; and Jianchun Wu;

Received 14 May 2019; Revised 5 August 2019; Accepted 23 August 2019; Published 10 September 2019

Academic Editor: Lorenzo Loffredo

Caption: FIGURE 1: Production, regulation, and biological effects of ROS. Mitochondria and NOXs are the main sources of [O.sub.2.sup.-]. [O.sub.2.sup.-] is formed by molecular oxygen that receives one single electron leaking from mitochondrial ETC or from NOXs. [O.sub.2.sup.-] is then rapidly converted into [H.sub.2][O.sub.2] by the corresponding SODs. [H.sub.2][O.sub.2] can be converted into [H.sub.2]O through intracellular antioxidants such as PRX, GPX, and CAT. When the [H.sub.2][O.sub.2] level is uncontrollably increased, OH' is further formed via the Fenton reaction with metal ions, thereby damaging biological macromolecules such as DNA, lipids, and proteins. In addition, [H.sub.2][O.sub.2] is a major signaling molecule participating in cellular physiological and pathological processes. The effects of ROS depend on their intracellular concentration. Normal cells typically have lower concentrations of ROS due to their normal metabolism; in normal cells, ROS act as signaling molecules to maintain homeostasis, such as by limiting cellular proliferation, differentiation, and survival. The increased metabolic activity of cancer cells produces high concentrations of ROS, leading to a series of tumor-promoting events, such as DNA damage, genomic instability, oncogene activation, sustained proliferation, and survival. Elevated ROS concentrations also result in the protective growth of cancer cells with enhanced antioxidant capacity to maintain tumor-promoting signaling. Increasing ROS levels to the toxicity threshold, such as by treatment with exogenous ROS inducers or antioxidant inhibitors, causes oxidative damage to cells and, inevitably, cell death.

Caption: FIGURE 2: Treatment strategy based on redox regulation. Compared to normal cells, cancer cells have increased levels of basal ROS, resulting in the maintenance of tumor-promoting signaling in these cells. Therefore, strategies for reducing ROS by using antioxidants to prevent carcinogenesis or delay tumor growth are theoretically feasible (however, most current clinical results are not supported). However, strategies for increasing ROS to toxic levels by using ROS inducers and/or inhibiting ROS scavengers can result in the specific killing of cancer cells (such approaches seem more promising than ROS reduction strategies).
TABLE 1: Components of TCMs targeted to decrease ROS levels and the
effects of these components in cells.

Components                                Herbs

Astragaloside IV                Milkvetch root (Huang Qi)

Benzyl                          Lepidii semen (Ting Li Zi)

Catalpol                  Rehmannia glutinosa libosch (Di Huang)

Crocin                      Crocus sativus L. (Zang Hong Hua)

Curcumin              Curcuma longa L. (Jiang Huang) Curcumae radix
                                         (Yu fin)

Dioscin                   Smilacis glabrae rhizoma (Tu Fu Ling)

Daphnetin               Daphne Korean nakai (Chang Bai Rui Xiang)

Ellagic acid                     Rubus idaeus (Fu Pen Zi)

Eriodictyol               Dracocephalum rupestre (Yan Qing Lan)

Epigallocatechin-                   Green tea (Lv Cha)

Isoliquiritigenin                   Licorice (Can Cao)

Luteolin              Chrysanthemi indiciflos (Ye fu Hua) Lonicerae
                               japonicae flos (fin Yin Hua)

Nexrutine                   Phellodendron amurense (Huang Bai)

Pedicularioside G           Pedicularis striata (Ma Xian Hao)

Resveratrol           Polygonum cuspidatwn (Hit Zhang) Fructus mori
                                       (Sang Shen)

Rutin                   Ruta graveolens L. (Yun Xiang) Fagopyrum
                           tataricum (L.) Gaertn (Ku Qiao Mai)

Saikosaponin-D                   Radix bupleuri (Chai Hu)

Sulforaphane                   Codonopsis radix (Dang Shen)

Tetramethylpyrazine          Chuanxiong rhizoma (Chuan Xiong)

Tanshinone II-A                  Radix salviae (Dan Shen)

Components                 Target cells           Biological effects

Astragaloside IV      Kidney proximal tubular          Mitigate
                            HK-2 cells          cisplatin-induced acute
                                                     kidney injury

Benzyl                 Leukemia HL-60 cells             Prevent
isothiocyanate                                   inflammation-related

Catalpol              Pheochromocytoma PC-12      Against LPS-induced
                               cells                   apoptosis

Crocin                 Melanoma B16F10 cells         Inhibition of

Curcumin                 Breast epithelial       Against PhlP-induced
                           MCF-10A cells             cytotoxicity

Dioscin               Ventricular H9c2 cells            Against

Daphnetin             Monocyte RAW264.7 cells   Against t-BHP-triggered
                                                 oxidative damage and

Ellagic acid              Ishikawa cells        Reduction of glycolytic
                                                     flux Against
                                                   cardiac oxidative

Eriodictyol           Pheochromocytoma PC-12       Against hydrogen
                               cells               peroxide-induced

Epigallocatechin-     Inner ear UB/OC-1 cells           Against
3-gallate                                          cisplatin-induced

                         Breast epithelial       Against PhIP-induced
                           MCF-10A cells         breast carcinogenesis

Isoliquiritigenin        Kidney epithelial              Against
                           LLC-PK1 cells           cisplatin-induced

Luteolin               Bronchial epithelial          Inhibition of
                           BEAS-2B cells            Cr(VI)-induced

Nexrutine             Pancreatic cancer cells    Inhibit autophagy and
                        Capan-2, MIAPaCa-2,     pancreatic cancer cell
                          AsPC-1, BxPC-3                growth

Pedicularioside G       Hepatoma SMMC-7721           Inhibition of
                          cells and HUVEC          angiogenesis and

Resveratrol             Pancreatic stellate     Inhibition of invasion,
                               cells                migration, and

                      Glioblastoma U87 MG and   Enhance the efficacy of
                           GBM8401 cells             temozolomide

Rutin                   Neuroblastoma IMR32           Ameliorates
                               cells              doxorubicin-induced
                                                memory deficits Against

Saikosaponin-D                   /                      Reduces

Sulforaphane           Bronchial epithelial     Against cadmium-induced
                           BEAS-2B cells            carcinogenesis

Tetramethylpyrazine   Kidney proximal tubular           Against
                            HK-2 cells             arsenite-induced

Tanshinone II-A       Monocyte RAW264.7 cells         Decrease H.
                        and stomach cancer          pylori-induced
                            MKN45 cells            inflammation and
                                                    gastric cancer

Components                     Molecular events              Reference

Astragaloside IV      T-SOD[up arrow], GSH-Px[up arrow],       [153]
                       CAT[up arrow]; KIM-1[down arrow],
                       MDA[down arrow], TNF-[alpha][down
                        arrow]; Nrf2f, HO-1[up arrow],
                            NF-[kappa]B[down arrow].

Benzyl                NADPH oxidase[down arrow], ROS[down      [154]
isothiocyanate                      arrow]

Catalpol               Bcl-2[up arrow], BAX[down arrow],       [155]
                         p-CaMK[down arrow], Ca2+[down
                           arrow]; CaMKII-dependent
                      ASK-l/JNK/p38 pathway [down arrow]

Crocin                 Tyrosinase[down arrow], MITF[down       [156]
                            arrow], ROS[down arrow]

Curcumin                Nrf2[up arrow], FOXO[up arrow];        [157]
                       BRCA-1, H2AFX, PARP-1, and P16[up
                         arrow]; Casp-3/9[down arrow]

Dioscin               miR-140-5p[down arrow]; ROS, MD A,       [158]
                       SOD, GSH, and GSH-Px[down arrow];
                       Nrf2 and Sirt2 pathway[up arrow]

Daphnetin              ROS[down arrow], MDA[down arrow];       [159]
                      SOD[up arrow], GSH/GSSG[up arrow];
                        JNK and ER[up arrow]; Nrf2/ARE
                               pathway[up arrow]

Ellagic acid          ROS[down arrow], NHE1[down arrow],       [160]
                        Na+/H+ exchanger activity[down
                           arrow], PHi[down arrow];

                       ROS[down arrow], MDA[down arrow],       [161]
                       XO[down arrow]; Casp-3, p-ERKl/2,
                      p-p38, and NF-[kappa]B[down arrow]

Eriodictyol           Nrf2, HO-1, [gamma]-GCS, and GSH[up      [162]
                      arrow]; Nrf2/ARE pathway[up arrow]

Epigallocatechin-        ROS[down arrow], ERK1/2[down          [163]
3-gallate                arrow], STAT3/STAT1[up arrow]

                      Ras/ERK/Nox/ROS pathway[down arrow]      [164]

Isoliquiritigenin        ROS[down arrow], Casp-3[down          [165]
                          arrow], Nrf2/HO-1[up arrow]

Luteolin                AP-1, HIF-l[alpha], COX-2, and      [166, 167]
                            iNOS[down arrow]; MAPK,
                       NF-[kappa]B, and EGF[down arrow];
                         proinflammatory cytokine[down
                        arrow]; Nrf2, HO-1, NADPH, and
                              SOD1/SOD2[up arrow]

Nexrutine                ROS[down arrow], LC3-II[down          [168]
                           arrow]; STAT3[down arrow]

Pedicularioside G     ROS[down arrow], VEGF[down arrow],       [169]
                               IL-8[down arrow]

Resveratrol             ROS/miR-21[down arrow], PTEN[up        [104]

                        ROS/ERK-mediated autophagy[down        [170]
                          arrow]; apoptosis[up arrow]

Rutin                  ROS/JNK/TNF/P38 MAPK pathway[down    [171, 172]

Saikosaponin-D           ROS, P38, and JNK/NF-[kappa]B         [173]
                              pathway[down arrow]

Sulforaphane           Nrf2[up arrow], ROS[down arrow],        [174]
                        protective autophagy[up arrow]

Tetramethylpyrazine     ROS[down arrow], GSH[up arrow],        [175]
                            apoptosis[down arrow],
                         proinflammatory signals[down
                       arrow], cytotoxic autophagy[down

Tanshinone II-A          NF-[kappa]B and MAPK(p38/JNK)         [176]
                       pathway[down arrow]; inflammatory
                       substance[down arrow]; apoptotic
                               protein[up arrow]

TABLE 2: Compounds of TCMs targeted to increase ROS levels and the
effects of these components in cancer cells.

Components                              Herbs

Aloe emodin                         Aloe (Lu Hui)

Atractyloside               Atractylodes lancea (Cang Zhu)

Baicalein                Scutellaria baicalensis (Huang Qin)

Berberine                Coptis chinensis Franch (Huang Lian)

Bufalin                 Bufo bufo gargarizans cantor (Chan Su)

Celastrol                 Tripterygii radix (Lei Gong Teng)

Cordycepin              Cordyceps sinensis (Dong ChongXia Cao)

Costunolide                  Aucklandiae radix (Mu Xiang)

Cucurbitacin E        Bolbostemae paniculati bulbus (Til Bei Mu)

Curcumin                    Curcuma longa L. (Jiang Huang)

Daidzein                        Glycine max (Hei Dou)

Emodin                        Rheum palmatum (Da Huang)

Epigallocatechin-                 Green tea (Lv Cha)

Escin                         Semen aesculi (Suo Luo Zi)

Eugenol                   Eugenia caryophyllata (Ding Xiang)

Evodiamine              Evodia rutaecarpa Bentham (Wu Zhu Yu)

Gambogic acid          Garcinia hanburyi Hook. f. (Teng Huang)

Germacrone                     Curcuma zedoaria (E Zhu)

Gypenoside               Gynostemma pentaphyllum Qiao Gu Lan)

Honokiol                    Magnolia officinalis (Hon Po)

Icariin               Epimedium brevicornum Maxim (Yin Yang Huo)

Isoalantolactone             Inula helenium (Tu Mu Xiang)

Luteolin                Chrysanthemi indiciflos (Ye fil Hua)
                        Lonicerae japonicae flos (fin Yin Hua)

Matrine                           Sophora flavescens

Neferine                      Ndumbo nucifera (Lian Hua)

Norcantharidin                    Mylabris (Ban Mao)

Oridonin                  Rabdosia rubescens (Dong Ling Cao)

Oroxylin A            Oroxylum indicum (Mu Hu Die) Scutellaria
                               baicalensis (Huang qin)

Plumbagin                  Plumbago zeylanica (Bai Hua Dan)

Resveratrol         Polygonum cuspi datum (Hu Zhang) Fructus Mori
                                     (Sang Shen)

Saxifragifolin D           Androsace umbellate (Hu Er Cao)

Sophoranone           Radix sophorae tonkinensis (Shan Dou Gen)

Tetrandrine              Stephania tetrandra radix (Fang fi)

Vitexin                     Vitex negundo L (Ma Bian Cao)

Components               Target cells           Biological effects

Aloe emodin         Lung cancer cells H460     DNA damage Apoptosis

                     Nasopharyngeal cancer         Cycle arrest
                    cells NPC-TW039, TW076

Atractyloside           Leukemia cells               Apoptosis

Baicalein             Breast cancer cells            Apoptosis

                     Colon/prostate cancer      Apoptosis/overcome
                       cells SW480; PC3          TRAIL resistance

Berberine              Lung cancer cells             Apoptosis
                     H1975, H1650, H1819,
                          A549, H1299

                      Liver cancer cells             Apoptosis
                        HepG2, Hepal-6

Bufalin               Breast cancer cells           Necroptosis
                       MCF-7, MDA-MB-231

                      Colon cancer cells             Autophagy
                         HT-29, Caco-2

Celastrol           Osteosarcoma cells HOS,     Apoptosis Autophagy
                     MG-63, U-20S, Saos-2          Cycle arrest

                      Breast cancer cells       Against doxorubicin
                       MCF-7, MCF-7/MDR             resistance

Cordycepin           Glioma cells Rat C6,     Apoptosis Cycle arrest
                      LN18, T98G, LN229,       Synergistic with TMZ

                     Gastric/colon cancer      DNA damage Apoptosis
                     cells SGC-7901; HT-29

Costunolide          Prostate cancer cells            Enhance
                         PC-3, DU-145           doxorubicin-induced

                     Ovarian cancer cells       Induce apoptosis of
                      MPSC1, A2780, SKOV3       platinum-resistant
                                                  cells Apoptosis

                      Colon cancer cells

Cucurbitacin E         Colorectal cancer      Cycle arrest Apoptosis
                      primary cell lines

Curcumin             Lung/prostate cancer            Apoptosis
                       cells A549, PC-3

                     Cervical cancer cells
                      C33A, CaSki, HeLa,

Daidzein              Breast cancer cells            Apoptosis

Emodin               Cervical cancer cells           Apoptosis

Epigallocatechin-   Malignant B-cell lines           Apoptosis
3-gallate             HS-sultan, RPMI8226

Escin                 Osteosarcoma cells        Autophagy Apoptosis
                       MNNG/HOS, Saos-2,
                         MG-63, U2-OS

Eugenol              Leukemia cells HL-60,           Apoptosis

Evodiamine            Glioma cells U87-MG       Apoptosis Autophagy
                                                   Cycle arrest

                     Cervical cancer cells

Gambogic acid         Colon cancer cells      Apoptosis/against drug
                        HCT-15, HCT-15R             resistance

                       Lung cancer cells         Synergistic with
                       A549,H460,H 1299              cisplatin

Germacrone            Breast cancer cells            Apoptosis

Gypenoside          Esophageal cancer cells          Autophagy
                         ECA-109, TE-1

Honokiol              Osteosarcoma/glioma       Apoptosis Autophagy
                    cells HOS, U20S; U87MG         Cycle arrest
                      Neuroblastoma cells
                       Neuro-2a, NB41A3

Icariin             Esophageal cancer cells          Apoptosis
                       EC 109, TE1 Liver
                    cancer cells SMMC-7721,
                        Bel-7402, L-02

Isoalantolactone    Esophageal cancer cells          Apoptosis
                     ECA109, EC9706, TE-1,

Luteolin              Liver cancer cells       Apoptosis DNA damage
                    HepG2; MDR cancer cells        Cycle arrest

Matrine             Pancreatic cancer cells   Cycle arrest Apoptosis
                       PANC-1, Miapaca-2

                      Liver cancer cells        Program cell death

Neferine            Lung cancer cells A549      Autophagy enhances
                                               autophagic cell death

Norcantharidin        Liver cancer cells             Apoptosis

Oridonin              Osteosarcoma cells             Apoptosis
                          MG-63, HOS

Oroxylin A            Colon cancer cells             Apoptosis
                        CaCo-2, HCT-116

Plumbagin             Colon cancer cells             Apoptosis
                    HT-29, HCT-116, Caco-2

Resveratrol           Lung/breast cancer        Apoptosis Autophagy
                      cells H1299, MCF-7

                     Prostate cancer cells           Apoptosis
                          LNCaP, PC-3

Saxifragifolin D      Breast cancer cells       Autophagy Apoptosis
                       MCF-7, MDA-MB-231

Sophoranone           Leukemia cells U937            Apoptosis

Tetrandrine          Leukemia cells K562,     Autophagy Cycle arrest
                           CMK, HEL               Differentiation

                    Live cancer cells Huh7,          Apoptosis
                        HepG2, BEL7402

Vitexin              Melanoma cells A375,     DNA damage Cycle arrest
                      Sk-Mel-5, Sk-Mel-28

Components                    Molecular events              Reference

Aloe emodin         ROS[up arrow], SOD[up arrow]; hMTH1,      [177]
                         hOGG1, and APE[down arrow]

                    Cyclin B1[up arrow], Cdc2[up arrow],      [178]
                     PARP[up arrow], Casp-3/8[up arrow]

Atractyloside         ROS[up arrow]; ER Ca2+[up arrow]        [179]

Baicalein           PLC-dependent Ca2+[up arrow], ROS[up      [180]
                    arrow]; Ca2+-associated apoptosis[up

                     ROS[up arrow], DR5[up arrow], TRAIL      [181]
                             receptor[up arrow]

Berberine             SREBP1[down arrow]; mitochondrial       [182]
                    dysfunction, ROS[up arrow], p-AMPK[up
                      arrow]; lipogenesis[down arrow]

                         p-PTEN, p-Akt, p-mTOR, and           [183]
                      p-PDK1[down arrow]; Fox01, Fox03,
                     Bim, Bax, Bax/Bcl-2, Casp-3/9, and
                     cl-PARP[up arrow]; p-JNK[up arrow],
                    ROS[up arrow]; SOD, CAT, and GSH[down

Bufalin                 RIP1/RIP3[up arrow]; ROS and          [184]
                     PARP-1[up arrow], RIP1/RIP3/PARP-1
                              pathway[up arrow]

                    ROS[up arrow], p-JNK[up arrow]; ATG5,     [185]
                      Beclin-1, LC3-II, and autophagic
                               flux[up arrow]

Celastrol                ROS/JNK pathway[up arrow],           [186]
                       Casp-3/8/9[up arrow]; LC3-II[up

                      HSF-1[up arrow], NF-[kappa]B[down       [187]
                          arrow], P-gp[down arrow]

Cordycepin             ROS[up arrow], GSH[down arrow];        [188]
                         p-GSK-3[beta][down arrow],
                         [beta]-catenin[down arrow].

                      DR3[up arrow], A3AR[down arrow],      [189, 190]
                     PI3K/Akt[up arrow], ROS[up arrow],
                     [DELTA[psi]m[down arrow]; p53, Bax,
                      Casp-3/8/1, and cl-PARP[up arrow]

Costunolide            ROS[up arrow], p-JNK[up arrow],        [191]
                     p-p38[up arrow], [DELTA][psi]m[down
                        arrow], Baxf, Bakf, Bcl-24.,
                       Bcl-xL[down arrow], Casp-3/9[up
                          arrow], cl-PARP[up arrow]

                      ROS[up arrow], Bcl-2[down arrow],       [192]
                            Casp-3/8/9[up arrow]

                      TrxR1[down arrow], ROS[up arrow],       [193]
                                ERS[up arrow]

Cucurbitacin E        ROS[up arrow], [DELTA][psi]m[down       [194]
                      arrow], GADD45[gamma][up arrow],
                       Cdc2[down arrow] Cyclin B1[down

Curcumin               TrxR2[down arrow]; Bax/Bcl-2[up        [195]
                     arrow], [DELTA][psi]m[down arrow],
                    cyto C[up arrow], Casp-3/9[up arrow]

                     p-PERK, IRE-1[alpha],GRP-78, ATF6,       [196]
                       and CHOP[up arrow]; Bax/Bcl-2,
                       Casp-3/9, and cl-PARP[up arrow]

Daidzein              ROS[up arrow], [DELTA][psi]m[down       [197]
                      arrow], Bcl-2[down arrow], Bax[up
                    arrow], cyto C[up arrow], Casp-7/9[up

Emodin                 ROS[up arrow], NF-[kappa]B[down      [198, 199]
                     arrow], AP-1[down arrow]., p-P38[up

Epigallocatechin-       Cyto C, Smac/DIABLO, AIF, and         [200]
3-gallate                    Casp-3/9[up arrow]

Escin               ROS/p38 MAPK[up arrow]; LC3 II, ATG5      [201]
                         ATG12 and Beclin[up arrow];
                    Bax/Bcl-2[up arrow], Casp-3/7/8/9[up

Eugenol               ROS[up arrow], [DELTA][psi]m[down       [202]
                    arrow], Bcl-2[down arrow]., cyto C[up
                          arrow] Casp-3/9[up arrow]

Evodiamine             Calcium/JNK signaling-mediated         [203]
                            autophagy[up arrow];
                             apoptosis[up arrow]

                    PTK/Ras-Raf-JNK[up arrow]; ROS/NO[up      [204]
                     arrow]; p53, p21, Cdc2, and cyclin
                                B1[up arrow]

Gambogic acid       [DELTA][psi]m[down arrow], cyto C[up      [205]
                    arrow], AIF[up arrow]; Bcl-2, Bcl-xl,
                     Mcl-1, XIAP and survin[down arrow];
                      p-JNK[up arrow], c-JUN[up arrow];

                     Casp-3/8/9, Fas and Bax[up arrow];       [206]
                      Bcl-2,XIAP, survivin[down arrow];
                     NF-[kappa]B, MAPK/HO-1 pathway[down

Germacrone            ROS[up arrow], [DELTA][psi]m[down       [207]
                     arrow]; Bax, JNK1, IKK[alpha], and
                     IKK[beta][up arrow]; Bcl-2, Bcl-xl,
                          Bim, and Bik[down arrow].

Gypenoside           ROS-induced ERS[up arrow], Ca2+[up       [208]
                      arrow]; P62[up arrow], autophagic
                              flux[down arrow].

Honokiol              GRP-78[up arrow], ROS[up arrow],      [209-211]
                    p-ERK1/2[up arrow]; LC3 II[up arrow]
                      ERS/R0S/ERK1/2 pathway[up arrow];
                        p53/PI3K/Akt/mTOR[down arrow]

Icariin               GSH[down arrow]; NADPH, Casp-9[up     [212,213]
                        arrow]; p-PERK, GRP-78, ATF4,
                     p-eIF2[alpha], and CHOP[up arrow];
                    PUMA[up arrow], Bax/Bcl-2[up arrow],
                    [DELTA][psi]m[down arrow], cyto C[up
                         arrow], Casp-3/9[up arrow],
                     cl-PARP[up arrow]; p-JNK[up arrow]

Isoalantolactone        ROS[up arrow], DR5[up arrow],         [214]
                     Casp-3/7/10[up arrow]; DR5-induced
                             extrinsic apoptosis

Luteolin               ROS[up arrow], PIG3[up arrow],       [215,216]
                    [DELTA][psi]m[down arrow], cyto C[up
                        arrow], Bax/Bcl-2[up arrow],
                      casp-3/9[up arrow] ROS[up arrow],
                       ATR/Chk2/p53 pathway[up arrow],
                     p38[up arrow], Bcl-2[down arrow].,
                           NF-[kappa]B[down arrow]

Matrine                ROS, p-ERK, p-JNK, and p-P38[up        [217]
                       arrow] Cyclin A, Dl, CDK2[down
                    arrow]; cyto C, Casp-3, cl-PARP, Bax,
                    and Bad[up arrow]; Bcl-2[down arrow]

                      [DELTA][psi]m[down arrow], ROS[up       [218]
                       arrow]; Fas[up arrow], Fas-L[up
                        arrow]; Casp-3[up arrow]; AIF
                           translocation[up arrow]

Neferine                ROS[up arrow], GSH[up arrow],       [219, 220]
                    PI3K/Akt/mTOR[down arrow], LC3-II[up
                      arrow] PI3K/Akt/mTOR pathway[down

Norcantharidin        ROS[up arrow], [DELTA][psi]m[down       [221]
                    arrow], cyto C[up arrow], Bcl-2[down
                    arrow] Bax, Casp-3/9, and cl-PARP[up

Oridonin              PPAR-[gamma][up arrow], Nrf2[down       [222]
                      arrow]; [DELTA][psi]m[down arrow]
                      Bax/Bcl-2[up arrow], Casp-3/9[up

Oroxylin A          UCP2[down arrow]; ROS, MPTP, cyto C,      [223]
                     AIF Casp-3/9 and cl-PARP[up arrow]

Plumbagin           ASKl/TRAF2[up arrow], JNK[up arrow] ;     [224]
                    mTORC1[down arrow] Bcl-2[down arrow]

Resveratrol          TIGAR[down arrow], GSH[down arrow],      [225]
                      ROS[up arrow], cl-PARP[up arrow]
                              LC3-II[up arrow]

                      TRXI[down arrow], TXNIP[up arrow]       [226]

Saxifragifolin D       LC3-II, Beclin-1, and Vps34[up         [227]
                     arrow]; ROS-mediated ERS[up arrow]

Sophoranone          ROS[up arrow], MPTP[up arrow], cyto      [228]
                        C[up arrow], p-JNK[up arrow],
                              Casp-3[up arrow]

Tetrandrine           ROS[up arrow], LC3 II[up arrow],        [229]
                       p-Akt[up arrow]; p21[up arrow],
                                p27[up arrow]

                     ROS[up arrow]; p-Akt, p-ERKl/2, and      [230]
                             p-JNK[down arrow].

Vitexin                 ROS, Bax, and PARP[up arrow];         [231]
                       Bcl-2[down arrow] p-ATM, p-ATR,
                    p-CHK2, p53, p21, and [gamma]-H2AX[up
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Author:Qian, Qiaohong; Chen, Wanqing; Cao, Yajuan; Cao, Qi; Cui, Yajing; Li, Yan; Wu, Jianchun
Publication:Oxidative Medicine and Cellular Longevity
Geographic Code:1CANA
Date:Sep 30, 2019
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