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Lung Cancers and the Roles of Natural Compounds as Potential Chemotherapeutic and Chemopreventive Agents.

The statistics reported by the World Health Organization (WHO) showed that lung cancer (including trachea and bronchus cancer) is one of the leading cause of deaths worldwide, causing about 1.7 million deaths in 2015 (1). Lung cancer can be due to inborn genetic defects, environmental and lifestyle factors. While inborn genetic defects have little contribution, both environmental and lifestyle factors play a pivotal role in causing lung cancer (2, 3). Asbestos, ionizing radiation, sulfur mustard, coal-tar pitch and tobacco smoking are some examples of environmental and lifestyle factors that serve as lung carcinogens (4). Tobacco smoking has been reported as the most influential risk factor for lung cancer cases in 90% of men and 80% of women (5). According to the International Agency for Research on Cancer, cigarette smoke contains 4000 identifiable chemicals with more than 60 chemicals are carcinogens (6). Polycyclic aromatic hydrocarbons (PAHs), N-nitrosamine, and aromatic amines are some of the most potent carcinogens that can be found in the cigarette smoke (7). Based on histological observation under the light microscopy, the two major groups of lung cancer are small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). NSCLC is further sub-divided into adenocarcinoma, squamous cell carcinoma and large cell carcinoma and others (8, 9). NSCLC is more dominant and makes up almost 85% of all lung cancers while SCLC counts for about 15% of all lung cancers (10). The most common subtypes of NSCLC are lung adenocarcinoma and lung squamous cell carcinoma (SCC) (11, 12).

The high mortality rate of lung cancer patients is due to the late diagnosis, with 70% of lung cancer cases identified in advanced stages (13). Late diagnosis has led to the failure of cancer treatment such as chemotherapy and radiotherapy (14). Early detection of lung cancer can substantially increase the chances of survival, where 70-90% of lung cancer patients with NSCLCs in early stage (stage I) that have been through surgical resection procedure can survive for five years (15, 16). Difficulty in the detection of an early stage of lung cancer, high cost in diagnostic tests, and invasive diagnostic procedures have been linked to the late diagnosis of lung cancer with most patients were diagnosed with stage IIIB and IV (17). A population-based study also showed that approximately 75% of lung cancer patients were diagnosed at the advanced stages such as stage III and IV (18). Tables 1 provides the information about the latest 8th TNM staging system for NSCLCs and the explanation for each stage that differentiate based on three characteristics including the primary tumour, involvement of lymph node and state of metastasis (19).

Treatments

The current treatment for lung cancer includes surgery, adjuvant, chemotherapy, and radiotherapy. The treatment of lung cancer depends on the histology and tumour stage. For example, in NSCLC, surgery will be done in patients with stage I, II, and IIIa if a tumour is resectable and depends on patient's toleration toward surgery (20). However, patients who have stage IIA, IIB, and IIIA NSCLC need subsequent treatment after the surgical procedure such as chemotherapy (21). Differently, the first line treatment for SCLC patients is chemotherapy (combination of platinum and etoposide) as surgical resection is rarely done due to early metastasis in this type of lung cancer. SCLC is very sensitive to chemotherapy during the initial treatment, but most of the SCLC patients (up to 90%) tend to develop chemoresistance. Besides, chemotherapy is also the only therapeutic option for the patients with metastatic NSCLC though most of the patients die as they cannot be treated through surgery procedure (22).

The only curative treatment for lung cancer is a radical surgery (23), yet, delay in diagnosis will lead to the poor prognosis. Unfortunately, 40% of the newly diagnosed NSCLC cases were advanced to stage IV and surgery alone is not enough for the treatment of lung cancer patients in the late stage. Cytotoxic chemotherapy is the first line therapy for NSCLC patients with stage IV that includes four to six cycles of platinum-based therapy such as cisplatin and carboplatin, with maintenance therapy afterwards in some patients is needed (24-26). There have been many reports on several complications, and side effects of conventional treatment approaches including the development of drug resistance in cancer cells due to the application of synthetic chemotherapeutic agents and the cost for synthetic drugs itself in cancer treatment is more expensive (20, 27). Furthermore, most of the drugs that used in current cancer treatments have many disadvantages such as rapid metabolism, non-selective, irritating nature, low aqueous stability, and others that consequently lead to the several adverse effects such as low quality of life in cancer patients and dose-limiting side effects (28). Alternative strategies needed to control this disease and there are many aspects should be improved in lung cancer treatments such as chemotherapy due to insignificant improvement in the efficacy of treatment in recent decades (29).

Chemoprevention

Sporn first introduced the term of chemoprevention in the early 1970s and defined it as the process of inhibition, suppression or reversion of cancer development or progression by using any natural or synthetic agents (30). Carcinogenesis is a complex event, and its development is a multistage process that consists of several phases: initiation, promotion, progression and lastly metastasis (31). For example, lung carcinogenesis derives from multiple steps involving a series of genetic and epigenetic alterations in pulmonary epithelial cells that lead to the changes in cell proliferation, differentiation, invasion, and metastasis (32).

Moreover, lung carcinogenesis also showed the characteristic of "field of cancerization" that refers to the adjacent tissue to neoplastic lesions that appear histologically normal, but this tissue consists of molecular abnormalities as in the tumours (33). Example of the "field of cancerization" during lung carcinogenesis is the formation of premalignant or injury in all airway of epithelial cells after exposure to the cigarette smoke (34, 35). This concept is further supported because of a single mutant epithelial cell in respiratory lining potentially to expand and extend into surrounding tissues in lung and lastly turns into malignancy. Even after smoking cessation, the expansion of premalignant field can still occur, and it is the vital step in lung carcinogenesis (36). Therefore, effective chemoprevention strategies are urgently needed as lung cancer risk is persistently increased even after the smoking cessation (former smokers) (37).

Natural agents such as phytochemicals are selectively targeting cancer cells, and even in small doses amount, the chemopreventive phytochemicals regularly act on cancer cells without affecting healthy cells (38). The natural agents from fruits and vegetables have shown several chemopreventive potentials in lung cancer. For example, one study revealed that the consumption of fruits and vegetables in current smokers could reduce the risk of getting lung cancer (39). Moreover, another study also showed the same finding where the higher consumption of cruciferous vegetables together with cigarette smoking control could lower the risk of lung cancer (40). Accordingly, there must be many potential candidates from natural sources that can be developed as cancer therapeutic and preventive agents to reduce the adverse effects of conventional cancer treatment.

Non-small cell lung cancer (NSCLC)

Lung Adenocarcinoma (AD)

Lung AD is a type of cancer that develops or arises from epithelial that line the small peripheral airways and categorised under the subtype of non-small cell lung cancer (NSLC). It is the most common type of all lung cancers (41, 42); hence lung adenocarcinoma is the most studied among other lung cancers. Amid all types of lung cancer, the incidence rate of lung adenocarcinoma in women is rapidly increased, but it is stabilised in men (43). Lung adenocarcinoma has a poor prognosis due to late diagnosis usually at the metastatic stage leading to failure in treatment (44). Although lung AD is the most frequent type of lung cancer seen in non-smokers, it also occurs in smoker patients (45). Other than that, in a multiracial Asian country, lung adenocarcinoma is more common in younger patients below the age of 40 years old compared to the older patients that have never smoked (46).

The precursor of lung AD involves various genetic changes with the most common are p53 mutation (50% to 70%), epidermal growth factor receptor (EGFR) kinase domain mutation (10% to 40%), Kristen Rat Sarcoma viral oncogene (KRAS) mutation (10% to 30%), and LBK1 mutation (34%) (47, 48). Both KRAS and EGFR mutations are rarely found in one tumour (49). KRAS mutation is more common in smokers with an early stage of lung adenocarcinoma or atypical adenomatous hyperplasia (AAH), and EGFR kinase domain mutation is much more common in nonsmokers with lung adenocarcinoma (47, 50). Moreover, 78% of lung AD patients had EGFR kinase domain mutation, but only 1.9% of patients had KRAS mutations among East Asian nonsmokers. EGFR plays various roles in a tumourigenic process including proliferation, apoptosis, angiogenesis and invasion (47).

Molecular targeted therapy such as targeted kinase inhibitors by gefitinib (Iressa) was performed in lung adenocarcinoma treatment, and this drug has been approved in Japan and the United States (51). In contrast, there is still no treatment targeting the KRAS mutations. As one of the most common genetic defects in lung AD, KRAS mutations can be the potential genetic abnormality to be targeted in the treatment of lung AD (52). There have been are many studies reported on the potential of natural agents to give effects as anti-cancer and chemoprevention on lung adenocarcinoma with various underlying mechanisms. Table 2 shows the summary of chemoprevention and chemotherapeutic recent researches on natural products against lung AD including the mechanisms of action. Squamous cell carcinoma (SCC)

Lung squamous cell carcinoma is an abnormal growth of cells from the bronchial epithelial cells through hyperplasia/metaplasia with the most common features are keratin pearls and/or intercellular bridges (65). The development of lung SCC is due to inhaled carcinogens that directly expose to the respiratory epithelium, and it is a sequential process that starts with squamous metaplasia, dysplasia, and carcinoma in situ (66). Historically, lung SCC is the most common type of lung cancer, but recently the lung adenocarcinoma has replaced the lung SCC as the most common type of lung cancer 12. Even though the reasons behind this trend is unknown, yet there are several possible factors such as diagnostic advances, changing from high-tar to low-tar filtered cigarettes and variations in smoking patterns (67). Cigarette smoking has a connection with all histologic types of lung cancer. However, a study done in 2001 revealed that smoking associated strongly with the lung SCC cases as compared to the carcinogenesis of lung adenocarcinoma (68). This strong association of smoking and lung SCC also has been proven by another study, where 96% of lung SCC patients in North America were ex-smokers or smokers (69).

None of the targeted therapies for lung SCC has been approved due to the lack of genomic understanding. Moreover, genomic studies on lung SCC is only now emerging, unlike multiple targeted therapies that have been identified in lung adenocarcinoma (70). For example, the therapeutic approaches that targeted on EGFR and echinoderm microtubule-associated protein like 4 --anaplastic lymphoma kinase (EML4-ALK) are only applicable in lung adenocarcinoma treatment, but not in lung SCC (71). For example, a clinical study in 2006 reported that bevacizumab that acts as endothelial growth factor (VEGF) inhibitors together with standard treatment (platin-based chemotherapy) increased the survival of NSCLC patients. The Eastern Cooperative Oncology Group (ECOG) performance status of patients with advanced NSCLCs also better compared to the standard treatment alone without bevacizumab. Unfortunately, the results are different for lung SCC patients, where there is no improvement in survival and ECOG performance status in lung SCC patients (72). Thus, the treatment that effective for lung adenocarcinoma does not promise the same results in lung SCC. More studies on lung SCC is needed due to the limited progression in lung SCC treatment as compared to lung adenocarcinoma, even though both are the most common types of lung cancer.

The most common genetic changes in lung SCC is the mutation of TP53 gene with 60 to 70% of lung SCC cases had this mutation, followed by phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) amplification that accounted for 33% of lung SCC cases (47). Apart from the alterations of TP53 and PIK3CA, Cancer Genome Atlas Research Networks 2012 revealed the list of most common genetic alterations in lung SCC including the mutations of histonelysine N-methyltransferase 2D(MLL-2), cyclin-dependent kinase 2A (CDKN2A), nuclear factor erythroid 2 like2 (NFE2L2), Kelch-like ECH-associated protein 1(KEAP1), and others. Others common genetic changes or alterations in lung AD such as mutations of EGFR and KRAS and fusion of anaplastic lymphoma kinase(ALK), but all these types of genetic changes are infrequent in lung SCC cases (71). Table 3 shows the the summary of chemoprevention and chemotherapeutic recent researches on natural products against lung SCC including the mechanisms of action.

Large cell carcinoma (LCC)

Large cell lung carcinoma (LCC) is a poorly differentiated subtype that often arises in peripheral lung tissue (77). In 2013, a team of researchers revealed that the tumour site of lung LCC is mostly located at the lung periphery with 81 cases (67%) out of 121 cases also showed that LCC cases have a strong relation with smoking habit in which about 92% of patients are smokers or former smokers (78).

Large cell neuroendocrine carcinoma (LCNC) is one example of lung large cell carcinoma (LCC), that shares the same characteristics with small cell lung cancer (SCLC) such as massive proliferation rates and neuroendocrine phenotype but lacks cytomorphology of SCLC (79, 80). LCNC is a rare type of lung cancer with estimated to account only for 3% of all lung cancers (81). The most common genetic changes in LCNC is the alteration of TP53 that accounts for 78% of LCNC cases. Others common genetic changes in LCNC including the alteration of few genes that encoded for retinoblastoma (RB1) protein, serine/threonine kinase II (STK II), Kelch-like ECH-associated protein 1 (KEAP1), and KRAS (80). Chemoprevention of lung LCC was excluded from the discussion due to limited chemopreventive study on lung LCC. Besides being a less common type of lung cancer, the limited chemopreventive study of lung LCC might be due to difficulties of developing the animal model that relevance to the human lung LCC. Table 4 shows the summary of chemotherapeutic researches of natural products against lung LCC and SCLC.

Small cell lung cancer (SCLC)

Small cell lung cancer (SCLC) is a type of lung cancer that develops from neuroendocrine-cell precursors. Some essential characteristics of SCLC are rapid cell growth, highly vascularized, genomic instability and early onset of metastatic. SCLC has the lowest survival rate among all type of lung cancers with only 3% to 8% of five-year survival rate, but the five-year survival rate of other types of lung cancers are more than 15% (84). Most of the SCLC patients are diagnosed with metastatic as the cancerous cells disseminated rapidly through the blood and lymphatic system (85). The response rates of SCLC towards both chemotherapy and radiotherapy is high, yet, patients with metastatic SCLC tends to develop treatment resistance (86, 87). The high risk of SCLC has a strong connection with cigarette smoking. Smoking cessation has an enormous impact on SCLC by reducing the risk of getting SCLC and increasing the survival rate among the patients with localised SCLC by almost 50% (88). Moreover, a study found that among 148 SCLC patients only 3 patients were non-smokers and another 145 patients were smokers (89).

The most common molecular genetic changes in SCLC are overexpression of BCL-2 and inactivation of p53 and retinoblastoma (Rb) protein. Inactivation of p53 and Rb protein has been found to account up to 90% of SCLC cases, and the inactivation of the two proteins can be caused by a mutation (gene deletion) (90). Other than differences in histological features between SCLC and NSCLC, these two subtypes of lung cancer also different in term of expression of neuroendocrine (NE) differentiation markers. NE differentiation markers only express in SCLC but not in NSCLC such as chromogranin A, neuron-specific enolase, synaptophysin, or neural cell adhesion molecule (91, 92). Study on chemoprevention of SCLC is minimal, especially on chemopreventive effects of natural compounds toward SCLC. Difficulties in developing a mouse model that relevance to human SCLC can be due to the complexity of this type of lung cancers such as SCLC tumors contain different tumor type of cell populations (cells heterogeneity) (93). Thus, the chemoprevention against SCLC was excluded from this review. Table 4 shows the summary chemotherapeutic researches of natural products against SCLC together with LCC.

CONCLUSION

Since numerous interventions have been done to improve the survival rate and burden of lung cancer patients, but lung cancer is still one of the major causes of cancer-related death. Other than focusing on improvement of treatment, chemoprevention of lung cancer has gained increasing popularity lately. Molecular targeted therapy specifically on each subtype of lung cancers might be one of the alternatives to improve the current treatments as it provides high efficacy approaches. Natural products are a great potential candidate for chemotherapeutic and chemoprevention as they have less harmful side effects and adverse reactions. Therefore, the discovery of new chemotherapeutic and chemopreventive agents are urgently needed to control lung cancer cases. This review of findings from in vitro and in vivo studies using human cell lines and experimental animal model specifically on each subtype of lung cancers may be a good source for further investigation, including the clinical study to discover the effective chemotherapeutic and chemoprevention agents for lung cancer.

http://dx.doi.org/10.13005/bpj/1617

(Received: 25 January 2018; accepted: 04 March 2019)

ACKNOWLEDGEMENTS

We gratefully acknowledge funding support from National University of Malaysia (UKM) grant of GUP-2016-079. Special thanks to Norizah Awang from Institute of Medical Research (IMR) of Malaysia for her support. No potential conflict of interest was reported by the authors.

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(82.) Hung JY, Hsu YL, Ko YC, Tsai YM, Yang CJ, Huang MS, et al. Didymin, a dietary flavonoid glycoside from citrus fruits, induces Fas-mediated apoptotic pathway in human non-small-cell lung cancer cells in vitro and in vivo. Lung Cancer.; 68(3):366-74 (2010).

(83.) Shieh JM, Cheng TH, Shi MD, Wu PF, Chen Y, Ko SC, et al. a-tomatine suppresses invasion and migration of human non-small cell lung cancer NCI-H460 cells through inactivating FAK/PI3K/Akt signaling pathway and reducing binding activity of NF-eB. Cell Biochemistry and Biophysics.; 60(3): 297-310 (2011).

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(96.) Lv C, Mioa L, Xu G, Wei S, Wang B, Huang C, et al. Wintilactone A as novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway. Cell Death & Disease.; 5; 4: e952 (2013).

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Omchit Surien, Ahmad Rohi Ghazali and Siti Fathiah Masre *

Biomedical Science Programme, Centre of Health and Applied Sciences, Faculty of Health Sciences, National University of Malaysia (UKM), 50300 Kuala Lumpur, Malaysia.

* Corresponding author E-mail: sitifathiah@ukm.edu.my
Table 1. 8th edition of the American Joint Commission on Cancer TNM
staging system for non-small cell lung cancer(NSCLC) and the
explanation for abbreviation of each stage (19).

Staging   TNM system (T: Primary tumor; N: Lymph node; M: Distant
          metastasis).

IA1       --N0 with any T1a

IA2       --N0 with T1b

IA3       --N0 with T1c

IB        --N0 with T2a

11A       --N0 with T2b

11B       --N0 with T3--N1 with any T1a, T1b, T1c, T2a, or T2b.

IIIA      --N0 with T4. --N1 with any T3 or T4--N2 with any T1a, T1b,
          T1c, T2a, or T2b.

IIIB      --N2 with any T3 or T4.--N3 with any T1a, T1b, T1c, T2a,
          or T2b.

IIIC      --N3 with any T3 or T4

IVA       --Any N0 to N3 with any M1a or M1b

IVB       --Any N0 to N3 with M1c

Explanation

1) Primary tumour(T)

T1a       Tumour in central airway but only superficial spreading
          (tumor equal or less than 1cm).

T1b       Tumour more than 1 cm but less than or equal to 2cm.

T1c       Tumour more than 2 cm but less than or equal to 3cm.

T2a       Involvement of visceral pleura, main bronchus, atelectasis
          to hilum, and no carina involvement.
          Tumour more than 3cm but less than or equal to 4cm.

T2b       Involvement of visceral pleura, main bronchus, atelectasis
          to hilum, and no carina involvement.
          Tumour more than 4 cm but less than or equal to 5cm.

T3        Invasion of tumour to the chest wall, pericardium, phrenic
          nerve; or one or more tumor nodules in same lobe with
          primary tumour; or tumour more than 5 cm but less than or
          equal to 7cm.

T4        Invasion of tumour to the mediastinum, diaphragm, heart,
          great vessels, recurrent laryngeal nerve, carina, trachea,
          esophagus, and spine; or tumor nodules in different
          ipsilateral lobe from where the primary tumor located; or
          tumour more than 7cm.

2)Lymph node(N)

N0        No of regional lymph node metastasis.

N1        Involvement of primary tumour that metastasis to the
          ipsilateral pulmonary or hilar lymph nodes.

N2        Involvement of primary tumour that metastasis to the
          mediastinal or subcarinal lymph nodes.

N3        Involvement of primary tumour that metastasis to the
          contralateral mediastinal, hilar or

          supraclavicular lymph nodes.

3) Distant metastasis(M)

M1a       Metastasis of primary tumour to the pleural or pericardial;
          or metastasis of tumor to the contralateral lobe from
          primary tumor.

M1b       Metastasis of tumour to any single extrathoraric.

M1c       Metastasis of tumour to multiple extrathoraric (1 or more
          organs).

Table 2. The summary of chemoprevention and chemotherapeutic effects
of natural products against lung AD (53-64).

Natural product     Sources                Mechanisms of action

Chemoprevention

Pterostilbene       Vitis vinifera         In vivo: * Pterostilbene
                    leaves and fruits;     decreased the epidermal
                    blueberries and        growth factor receptor EGFR
                    cranberries            expression and also
                                           decreased the expression of
                                           other EGFR mediators such
                                           as Akt/mTOR, ERK1/2, Stat-3,
                                           and NF[kappa]B.

                                           * Pterostilbene also induced
                                           apoptosis by decreasing the
                                           level of caspase-3 and
                                           LC3-II.

p-escin             Horse chestnut seeds   In vivo: * Reduced the
                    (Aesculus              number of tumours in a
                    hippocastanum).        mouse model. a-escin induced
                                           cell cycles arrest by
                                           reducing the expression of
                                           ALDH1A1, p-Akt, RhoA, and
                                           ROCK proteins. However,
                                           it increased the expression
                                           of p21 protein and reduced
                                           the level of PCNA.

Cucurbitacin B      Cucurbitaceae plants   In vitro: * CuB induced cell
(CuB)               such as fruit of       cycle arrest at G2/M phase
                    L.graveolense Roxb.    and apoptosis.

                                           In vivo: * Reduced the
                                           tumour multiplicity and
                                           PCNA-positive cells.

                                           In vitro and in vivo: *
                                           Upregulation of p16 and p21
                                           proteins expression and
                                           downregulation of tumour
                                           suppressor proteins such as
                                           c-myc, KRAS, and hTERT.

                                           * CuB inhibited the
                                           expression of DNMTs and
                                           histone deacetylase (HDACs).

Chemotherapeutic

Curcumin            Rhizome of             In vitro: * Curcumin
                    Curcumalonga.          treatment inhibited human
                                           lung adenocarcinoma derived
                                           cells (H441 cells) by
                                           suppressing the activation
                                           of the Stat-3 pathway.

Honokiol            Magnolia               In vitro: * Inhibited cell
                    grandiflora.           growth and induced cell
                                           cycle arrest at the
                                           G1 phase of A549 and H1299
                                           cell lines.

                                           * Repressed histone
                                           deacetylase (HDAC) activity
                                           and class 1 HDACs protein
                                           expression, but increased
                                           the activity of HATs.

                                           In vivo: * Inhibited tumor
                                           growth of A549 and H1299
                                           cell lines in a xenograft
                                           model. Induced apoptosis by
                                           downregulating Bcl-2 and
                                           Bcl-xl proteins expression.

                                           * The levels of class I
                                           HDACs and HDACs activity
                                           also decreased in this in
                                           vivo study.

Emodin              Roots and rhizomes     In vitro: * Emodin
                    Rheum palmatum L.      suppressed the
                                           proliferation of A549 cell
                                           lines by activation of
                                           ERK1/2 and downregulation
                                           of ERCC1 and Rad51 proteins
                                           expression that led to
                                           cytotoxicity.

Diosein             The roots of           In vitro: * Inhibited
                    Polygonatum            proliferation of A549 cell
                    zanlanscianense        lines by causing DNA damage
                    Pamp.                  and cell cycle arrest at S
                                           phase.

                                           * Diosein induced apoptosis
                                           by upregulating the
                                           pro-apoptotic proteins
                                           expression (Bax, Bak, and
                                           Bid). Downregulated the
                                           anti-apoptotic proteins
                                           expression (Bcl-2 and
                                           Bcl-xl). Increased the
                                           caspase-3 and caspase-6
                                           activities.

Piperine            Black pepper           In vitro: * Piperine
                    (Piper nigrum) and     inhibited the proliferation
                    long pepper            of A549 cell lines by
                    (Piper longum).        causing cell cycle arrest at
                                           the G2/M phase via p53
                                           dependent mitochondrial
                                           signalling pathway.

                                           * Induced apoptosis by
                                           activating caspase-3 and
                                           caspase-9, increased BAX
                                           and p53 proteins expression
                                           and downregulated Bcl-2
                                           protein expression.

Plumbagin (PL)      Plumbago zeylanica     In vitro:* Inhibited
                    L.                     proliferation of A549 and
                                           H23 cell lines by causing
                                           apoptosis and cell cycle
                                           arrest at G2/M phase.*

                                           * Cell cycle arrest by
                                           downregulating the
                                           expression of cyclin B1 and
                                           Cdc2, but upregulated the
                                           expression of p53 and p21.*

                                           * Induction of apoptosis by
                                           downregulating the
                                           expression of Bcl-2 and
                                           upregulating the expression
                                           of Bax and cytochrome c.
                                           Increased the levels of
                                           cleaved caspase-3 and 9.*

                                           * PL also increased the
                                           reactive oxygen species
                                           (ROS) production.*

                                           * Inhibited PI3K/Akt/mTOR
                                           pathway to induce autophagy
                                           as well.

TXA9                The roots of           In vitro: * Induced
                    Streptocaulon          apoptosis by increasing the
                    juventas.              level of Fas protein,
                                           Fas-associated death domain
                                           (FADD) and enzymes caspase-3
                                           and caspase-8.

                                           In vivo: * Inhibited tumour
                                           growth in a xenograft model.

Epigallocatechin    Green tea              In vitro: * EGCG inhibited
-3-gallate                                 nicotine-induced migration
(EGCG)                                     and invasion of A549 cells
                                           by suppressing the level of
                                           HIF-1a, vascular endothelial
                                           growth factor (VEGF), COX-2,
                                           p-Akt, p-ERK and vimentin
                                           proteins expression.

                                           * EGCG also downregulated
                                           expression of p53 and
                                           p-catenin proteins.

Picropodophyllin.   Mayapple plant         In vitro: * Inhibited
                    family                 proliferation of A549 and
                    (Podophyllum           H1299 cell lines by
                    peltatum).             repressing the expression
                                           of insulin-like growth
                                           factor 1 (IGF-1R) and
                                           decreasing the p-Akt and
                                           MAPK. Induced apoptosis by
                                           increasing the level of
                                           caspase 3, 7 and PARP
                                           proteins.

Natural product     Reference

Chemoprevention

Pterostilbene       Chen et al. 2012 (53).

p-escin             Patlolla et al. 2013(54).

Cucurbitacin B      Shukla et al. 2015 (55).
(CuB)

Chemotherapeutic

Curcumin            Alexandrow et al. 2012 (56).

Honokiol            Singh et al. 2012 (57).

Emodin              He et al. 2012 (58).

Diosein             Wei et al. 2013 (59).

Piperine            Lin et al. 2014 (60).

Plumbagin (PL)      Li et al. 2014 (61).

TXA9                Xue et al. 2015 (62).

Epigallocatechin    Shi et al. 2015 (63).
-3-gallate
(EGCG)

Picropodophyllin.   Zhang et al. 2015 (64).

* EGFR = epidermal growth factor receptor; Akt/mTOR = protein kinase
B/mammalian target of rapamycin (mTOR); ERK 1/2=
extracellular-signal-regulated kinase; ALDH1A1= aldehyde dehydrogenase
1A1= ALDH1A1; Stat-3= signal transducer and activator of
transcription3; LC3-II= microtubule-associated proteins 1A/1B light
chain 3B-11; p-AKT= phospho-Akt; RhoA = Ras homolog gene family member
A; ROCK = Rho-associated protein kinase; p21= cyclin-dependent kinase
inhibitor 1; hTERT= human telomerase reverse transcriptase;
KRAS = Kristen rat sarcoma 2 viral oncogene homolog; DNMTs= DNA
methyltransferase; HDACs= histone deactylases; Stat-3= signal
transducer and activator of -3; HDAC= histone deacetylase;
HATs= histone acetyltransferases;Bcl-2= B-cell lymphoma 2;
Bcl-xl= B-cell lymphoma-extra large; ERK 1/2=
extracellular-signal-regulated kinase; ERCC1=excision repair
cross-complementation group 1; RAD51= RAD51 recombinase; BAX=bcl-2-like
protein 4; Cdc2=cyclin-dependentkinase 1; PI3K=phosphoionositide
3-kinase;FADD=Fas-associated protein with death domain; HIF-1a=hypoxia
inducible factor 1 alpha; VEGF=vascular endothelial growth factor ;
COX-2= cyclooxygenase-2; MAPK=mitogen activated protein kinases;
PARP= poly(ADP-ribose) polymerase

Table 3. The summary of chemoprevention and chemotherapeutic effects
of natural products against lung SCC (58, 64, 73-76).

Natural products    Sources            Mechanisms of action

Chemoprevention

Honokiol            Bark of            In vivo:* Honokiol interrupted
                    Magnolia tree.     the mitochondrial function by
                                       causing inhibition of
                                       mitochondrial respiration
                                       leading to a decreased in ATP
                                       levels. The decreased in ATP
                                       levels activated the AMPK and
                                       lastly inhibited the tumour
                                       growth. *

                                       * Honokiol enhances the ROS
                                       production in mitochondria. *

                                       * Induction of apoptosis by
                                       increasing the level of cleaved
                                       caspase-3.

Picropodophyllin.   Mayapple           In vivo: * Reduced the tumour
                    plant family       load and multiplicity in
                    (Podophyllum       benzo(a)pyrene-induced lung
                    peltatum).         tumours in a mouse model by
                                       increasing the levels of cleaved
                                       caspase-3 apoptotic protein.

Vitamin D3                             In vivo: Vitamin D3 inhibited
                                       the proliferation rate by
                                       reducing the levels of Ki67
                                       protein.*

                                       * Vitamin D3 induced the
                                       anti-inflammatory activity by
                                       reducing the expression of IL-6,
                                       and the white blood cell (WBC)
                                       counts.

Chemotherapeutic

Emodin              Roots and          In vitro: * Emodin inhibited the
                    rhizomes           proliferation of SK-MES-1 cell
                    Rheum              lines (human lung squamous
                    palmatum L.        carcinoma cells). Emodin
                                       activated the ERK1/2 and
                                       downregulated the expression of
                                       ERCC1 and Rad51 proteins that
                                       caused cytotoxicity.

Alantolactone       Inula helenium     In vitro: * Inhibited SK-MES-1
                    L. roots.          cells growth by causing
                                       apoptosis and cell cycle arrest
                                       at the G0/G1 phase.*

                                       * Apoptosis- Downregulated the
                                       expression of Bcl-2, procaspase
                                       9 and 3. Upregulated the
                                       expression of Bax, cleaved
                                       caspase-3, and PARP.

                                       * Cell cycle arrest-
                                       Downregulated the expression of
                                       CDK4, CDK6, cyclin D3, and
                                       cyclin D1. Upregulated the
                                       expression of p21 and p27.

Custonolide         Compositae         In vitro: * Induced cell cycle
                    and Magnoliaceae   arrest at the G1/S phase and
                    plant families.    apoptosis in SK-MES-1 cell
                                       lines.*

                                       * Apoptosis by downregulating
                                       Bcl-2 and procaspase-3
                                       expression and upregulating Bax
                                       and cleaved PARP proteins
                                       expression.*

                                       * Caused cell cycle arrest by
                                       upregulating p53, p21, and p27
                                       expression, and downregulating
                                       pRB proteins.

Natural products    Reference

Chemoprevention

Honokiol            Pan et al.
                    2014(73).

Picropodophyllin.   Zhang et al.
                    2015 (64).

Vitamin D3          Mazzilli
                    et al. 2015
                    (74).

Chemotherapeutic

Emodin              He et al.
                    2012 (58).

Alantolactone       Zhao et al.
                    2015 (75).

Custonolide         Hua et al.
                    2016 (76).

* ATP= adenosine triphosphate; AMPK= 5' AMP-activated protein kinase;
Ki-67cell proliferation antigen Ki-67; IL-6 = interleukin-6;
ROS=reactive oxygen species. ERK1/2=extracellular signal-regulated
kinases 1/2; Rad51=DNA repair protein Rad51;ERCC1=DNA excision repair
protein ERCC-1; CDK4=cyclin dependent kinase -4; CDK6; cyclin
dependent kinase-6;pRB=phosho-retinoblastoma protein; p21=cyclin
dependent kinase inhibitor 1; p53=tumor suppressor p53; p27cyclin
dependent kinase inhibitor 1B.

Table 4. The summary of chemotherapeutic researches of natural products
against lung LCC and SCLC (59, 82, 83, 94-97)

Natural products   Sources               Mechanisms of action

Lung large cell carcinoma (LCC)

Didymin            Flavonoid glycoside   In vitro: * Inhibited H460
                   from citrus fruits.   cells growth by inducing
                                         apoptosis. *

                                         * Induced apoptosis by down
                                         regulating the expression of
                                         Fas/Apo-1 receptor and
                                         Fas-ligand. Didymin also
                                         activated the caspase-8.

a-tomatine         Lycopersicones        In vitro: ** a-tomatine showed
                   culentum Linn.        anti-metastatic effects on
                                         NCI-H460 cell lines.--Reduced
                                         the mRNA level and MMP-7
                                         protein expression. *

                                         * a-tomatine suppressed
                                         degradation and
                                         phosphorylation of DNA-binding
                                         activity of NF-eB and
                                         FAK/PI3K/Akt signalling
                                         pathway.

Diosein            Polygonatum           In vitro: * Inhibited
                   zanlanscianense       proliferation and induced
                   Pamp                  apoptosis in NCI-H460 cells.

                                         * Inhibited cell growth by
                                         causing DNA damage and cell
                                         cycle arrest at the S phase. *

                                         * Apoptosis: upregulated the
                                         expression of pro-apoptotic
                                         proteins (Bax, Bak, and Bid).

                                         * Downregulated the
                                         expression of anti-apoptotic
                                         proteins (Bcl-2 and Bcl-xl).

                                         * Increased the caspase-3
                                         and caspase-6 activities.

Small cell lung cancer(SCLC)

Curcumin           Rhizome of            In vitro: ** Inhibited cell
                   Curcumalonga          proliferation, migration and
                                         invasion of human small cell
                                         lung carcinoma (NCI-H446 cell
                                         line). *

                                         * Curcumin downregulated the
                                         expression of STAT3 by
                                         inhibiting the IL-6 leading to
                                         the inhibition of STAT3
                                         phosphorylation. *

                                         * Induced cell cycle arrest at
                                         the G2/M phase by
                                         downregulating the expression
                                         of Survivin, Bcl-xL and Cyclin
                                         B1. *

                                         * Depressed the migration and
                                         invasion of cells by
                                         suppressing the levels of
                                         VEGF, MMP-2 and MMP-7 and
                                         ICAM-1.

Catechins          Green tea             In vitro: * Caused cell cycle
                                         arrest at the G2/M phase of
                                         NCI-H466 cell lines. *

                                         * Upregulated the expression
                                         of let-7a-1 and let-7g protein
                                         leading to the downregulation
                                         of C-MYC and LIN-28 expression
                                         and induced cell cycle arrest.

Diosein            The root of           In vitro: * Inhibited cell
                   Polygonatum           proliferation and induced
                   zanlanscianense       apoptosis in NCI-H446 cells. *
                   Pamp
                                         * Anti-proliferation: induced
                                         DNA damage and cell cycle
                                         arrest at the S phase. *

                                         * Apoptosis: upregulated the
                                         expression of pro-apoptotic
                                         proteins (Bax, Bak, and Bid).
                                         Downregulated the expression
                                         of anti-apoptotic proteins
                                         (Bcl-2 and Bcl-xl). Diosein
                                         also increased the caspase-3
                                         and caspase-6 activities.

Wentilactone A     Marine-derived        In vitro: * Induced apoptosis
(WA)               endophytic fungi      and cell cycle arrest at the
                   Aspergillus wentii.   G2/M phase in NC1-H446 cell
                                         lines.

                                         * Induced cell cycle arrest by
                                         downregulating the expression
                                         of cyclin B1, cdc2, p-cdc2,
                                         cdc25C and p-cdc25C. WA
                                         increased the phosphorylation
                                         of ERK, JNK, p38 to activate
                                         the mitogen-activated
                                         protein(MAP) kinase
                                         signalling cascades. WA also
                                         induced the expression of p53,
                                         p21 and ROS production to
                                         induce cell cycle arrest. *

                                         * Apoptosis- Downregulated the
                                         expression of Bcl-2 and Mcl-1,
                                         but upregulated the expression
                                         of Bax, Bad, cleaved caspase-2
                                         and caspase 7.

Evodiamine         Evodia                In vitro: * Induced cell cycle
                   rutaecarpa            arrest at the G2/M phase and
                                         apoptosis in H446 and H1688
                                         cell lines. *

                                         * Increased the ROS production
                                         and activities of caspase 8,
                                         9 and 3. *

                                         * Increased the expression of
                                         cytochrome C, caspase 3, 8, 9,
                                         and Bax proteins, and
                                         decreased the expression of
                                         Bcl-2 protein.

Natural products   Reference

Lung large cell carcinoma (LCC)

Didymin            Hung et al.
                   2010 (82).

a-tomatine         Shieh et al.
                   2011 (83).

Diosein            Wei et al.
                   2013 (59).

Small cell lung cancer (SCLC)

Curcumin           Yang et al.
                   2012 (94).

Catechins          Zhong et al.
                   2012 (95).

Diosein            Wei et al.
                   2013 (59).

Wentilactone A     Lv et al.
(WA)               2013 (96).

Evodiamine         Fang et al.
                   2014 (97).

* Apo-1=Apoliprotein A1; MMP-7= matrix metalloproteinase-7;
NF-ka= nuclear factor kappa-light-chain enhancer of activated B
cells; FAK= focal adhension kinase; PI3K= phosphatidylinositol
3-kinase; Akt= protein kinase B; Bax= Bcl-2 associated X protein;
Bak= Bcl-2 homolog antagonist/killer; Bid=BH3 interacting-domain
death agonist; Bcl-2= B cell lymphoma 2; Bcl-xL= B cell lymphoma
extra large. STAT3= Signal transducer and activator of transcription 3;
IL6+interleukin 6; VEGF=vascular endothelial growth factor; MMP=matrix
metalloproteinase; ICAM-1= intracellular adhension molecule 1;
LIN28= Lin-28 homolog A protein; cdc25c= M-phase inducer phosphatase 3;
ERK= extracellular-signal regulated kinase; JNK= c-Jun N-terminal
kinases; ROS= reactive oxygen species; Bax= Bcl-2 associated X protein;
Bak= Bcl-2 homolog antagonist/killer; Bid=BH3 interacting-domain
death agonist; Bcl-2= B cell lymphoma 2; Bcl-xL= B cell lymphoma extra
large; Bad; Bcl-2 -associated death promoter
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Author:Surien, Omchit; Ghazali, Ahmad Rohi; Masre, Siti Fathiah
Publication:Biomedical and Pharmacology Journal
Date:Mar 1, 2019
Words:8483
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