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Natural Products as Adjunctive Treatment for Pancreatic Cancer: Recent Trends and Advancements.

1. Introduction

Pancreatic cancer is a type of common malignant tumors with high occurrence in the world. Due to the high rate of invasion and malignancy and asymptomatic development, pancreatic cancer is highly lethal. Data from Global Cancer Statistics in 2012 indicated that pancreatic cancer was the seventh leading death cause from cancer in both men and women worldwide [1]. In the developed countries, pancreatic cancer was the fifth/fourth leading death cause from cancer in men and women, respectively. In the developing countries, pancreatic cancer was the eighth/tenth leading death cause from cancer in men and women, respectively [1]. The patients with pancreatic cancer had poor survival rate with less than 5% of patients surviving 5 years after diagnosis. In 2016, it was estimated that 53,070 patients will be diagnosed with pancreatic cancer and 41,780 patients with pancreatic cancer will die in the United States, most of them dying within first year of diagnosis [2]. According to the 2015 oncology annals, pancreatic cancer in China was the ninth/sixth leading death cause from cancer for men and woman, respectively. About 90,100 patients were diagnosed with pancreatic cancer and 79,400 patients in China with pancreatic cancer died in 2015 [3]. Despite recent improvements of diagnostic techniques, most pancreatic cancer patients were diagnosed at advanced states. Most patients with pancreatic cancer, who were diagnosed annually, died within a year of diagnosis. So far, there are no adequate therapies for treating the patients with pancreatic cancer.

Surgery is a pivotal curative therapeutic approach for most patients with pancreatic cancer. However, the success rate of resection surgery remains very low because about 80%-85% patients with diagnosed with pancreatic cancer were already in an advanced stage [4]. So, only 15%-20% of patients with pancreatic cancer are eligible for surgical resection after being primarily diagnosed. Standard surgical procedures include pancreaticoduodenectomy (pylorus-preserving or stomach-preserving) for tumors of pancreatic head and distal pancreatectomy with splenectomy for tumors arising in the tail or body of the pancreas [4]. Radical resection, alone or in combination with other therapy, is the only way to eradicate pancreatic cancer. Only 10%-20% of patients with pancreatic cancer, who have radical resection, can survive 5 years. So, it is necessary to underscore the need for better preoperative staging and more effective systemic therapy [5]. Therefore, chemotherapy and radiotherapy are considered as the standard treatment approaches for the patients with unresectable pancreatic cancer, especially for locally advanced or metastatic inoperable patients with pancreatic cancer.

In the past three decades, the standard therapeutic drugs for pancreatic cancer were fluoropyrimidine drug 5-fluorouracil (5-FU) and the antimetabolite drug gemcitabine [6]. Since 5-fluorouracil (5-FU) was generated 50 years ago, only the incremental changes in clinical outcomes of pancreatic cancers were made. 5-Fluorouracil (5-FU) was the first agent to be widely used to treat advanced pancreatic cancer, but the success rates of 5-FU were <20% and it was not known whether 5-FU could provide significant palliative benefits. Gemcitabine, which is now widely accepted as the golden-standard drug prescribed for the patients suffering from locally advanced (stage II or stage III) or metastatic (stage IV) pancreatic cancer, is an analog of the pyrimidine nucleotide deoxycytidine [7]. Although gemcitabine offered only an extension of ~1.5 months in median survival, gemcitabine replaced 5-fluorouracil (5-FU) as the standard firstline chemotherapeutic agent since it was approved by the Food and Drug Administration (FDA) in 1996 [7]. Current treatment modalities for the advanced pancreatic cancer include gemcitabine, as a single agent or in combination with multiple chemotherapeutic agents. Unfortunately, most patients with locally advanced and metastatic pancreatic cancers could not benefit from the monotherapy of gemcitabine. Though many clinical trials had been conducted to ascertain the optimum therapy utilizing gemcitabine in combination with multiple chemotherapeutic agents such as 5-FU, capecitabine, pemetrexed, topoisomerase inhibitors, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, erlotinib, bevacizumab, irinotecan, exatecan, platinum compounds (cisplatin and oxaliplatin), and taxanes (paclitaxel and docetaxel), almost none of them was proven to be more effective, in comparison with gemcitabine as a single agent for treating pancreatic cancer [8]. In 2005, a four-drug regimen (gemcitabine, 5-fluorouracil, epirubicin, and cisplatin) was shown to improve the progression free survival and the overall survival of the patients with pancreatic cancer, compared with single-agent gemcitabine [8]. In 2011, a new treatment regimen FOLFIRINOX (a combination of 5-FU, leucovorin/folinic acid, oxaliplatin, and irinotecan) was demonstrated as superior survival outcomes of the patients with pancreatic cancer, compared with single-agent gemcitabine, which led to the adoption of FOLFIRINOX as the preferred option for the patients [8]. A trial comparing gemcitabine/nab-paclitaxel (nanoparticle albumin-bound paclitaxel) with gemcitabine alone showed a statistically significant survival benefit for the new doublet to introduce another option for the treatment of advanced pancreatic cancer [8].

Radiotherapy is often used to combine with systemic chemotherapy in oncology centers of USA. Radiotherapy exhibits a substantial advantage with respect to local control and improving the resectability rate after downstaging. Nonetheless, the approach has not significantly improved survival rates of the patients with unresectable pancreatic cancer. Moreover, specific radiotherapy modalities, such as stereotactic radiotherapy, TOMO, and intensity-modulated radiotherapy, have been applied to treat pancreatic cancer and survival outcomes of the patients with pancreatic cancer are partially improved [9]. However, compared with tumors in other sites, the overall survival of the patients with pancreatic cancer is unsatisfactory and the toxicity of radiotherapy is obvious. The poor prognosis of the patients with pancreatic cancer has been attributed to its late diagnosis, limitation of surgical resection, early metastases, aggressive local invasion, and robust resistance to chemotherapy and radiotherapy [9]. Hence, additional therapeutic approaches for treating pancreatic cancer are critical.

Complementary and alternative medicines, such as gene therapy, immunotherapy, targeted therapy, neoadjuvant therapy, and natural products/herbal medicines, may benefit the patients with pancreatic cancer as a supplementary therapy [10]. Of all complementary and alternative medicines, natural products/herbal medicines, such as Chinese herbal medicine, have become popular in the patients with advanced cancer, due to its efficacy and low toxicity [10]. Recent research works indicated that natural products/herbal medicines, such as Chinese herbal medicine, could provide additional strategies for monotherapy or combination treatments of various cancer types, including pancreatic cancer. Indeed, more than 60% of the current anticancer chemotherapeutic drugs used in clinic were initially developed from natural products/herbal medicines [11]. Natural products/herbal medicines, combined with conventional chemotherapy and radiotherapy, may enhance anticancer therapeutic efficacy and reduce the side effects [12]. In this context, the use of natural products/herbal medicines, as a supplementary approach, to treat pancreatic cancer holds a great promise.

Based on the published papers (up to July 15, 2016) searched in PubMed using the key words "natural product AND combination AND pancreatic cancer," we summarized the beneficial effects of natural products/herbal medicines, such as Chinese herbal medicine, in combination with conventional chemotherapy for the patients with unresectable pancreatic cancer in preclinical and clinical trials in this review. The detailed information of the current review includes (1) combination of natural products with gemcitabine, (2) combination of natural products with other chemotherapeutic agents, (3) combination among natural products, and (4) combination of natural products in early phases of clinical trials.

2. Combination of Natural Products with Gemcitabine

Irofulven (MGI 114, HMAF, 6-hydroxymethylacylfulvene), a novel cytotoxic agent synthesized from the sesquiterpene mushroom metabolite of the natural product illudin S, has a unique mechanism of action involving the formation of macromolecule adduct, cell cycle arrest of S-phase, and induction of apoptosis [49]. Phase I clinical combination trial study of irofulven and gemcitabine in the patients with advanced solid tumor was underway [50]. Van Laar et al. showed similar marked activity of irofulven against pancreatic xenografts which was observed at lower total doses of an intermittent dosing regimen, compared to consecutive daily dosing [51]. Further, enhanced antitumor activity was observed when irofulven and gemcitabine were combined against the MiaPaCa pancreatic xenograft model, which indicated at least an additive interaction compared to single-agent activity. Psorospermin, a natural product isolated from the stembark and roots of the African plant Psorospermum febrifugum, had the activity against drug-resistant leukemia lines and AIDS-related lymphoma [52, 53]. Fellows et al. showed that psorospermin had the same effect as gemcitabine in inhibiting the growth of tumor in vivo in the MiaPaCa pancreatic xenograft model. Moreover, psorospermin combined with gemcitabine was found to have an at least additive effect in slowing the growth of MiaPaCa pancreatic cancer cells [54]. 3,3-Diindolylmethane (DIM) is a natural compound which can be easily obtained by consuming the cruciferous vegetables. Banerjee et al. present in vitro and in vivo preclinical evidence supporting chemosensitization of pancreatic cancer cellsbyDIM [13]. DIM potentiates chemosensitization and killing of pancreatic cancer cells by downregulation of constitutive as well as drug-induced activation of NF-kappaB and its downstream genes (XIAP, Bcl-xL, survivin, and cIAP). Compared with monotherapy, DIM pretreatment of pancreatic cancer cells resulted in a significantly increased apoptosis with suboptimal concentrations of chemotherapeutic agents such as gemcitabine, cisplatin, and oxaliplatin. Thymoquinone is a bioactive compound extracted from the oil of folklore medicine black seed (Nigella sativa). Banerjee et al. reported the chemosensitizing effect of thymoquinone to conventional chemotherapeutic agents (gemcitabine and oxaliplatin) both in vitro and in vivo using an orthotopic model of pancreatic cancer [14]. By downregulation of nuclear factor-kappaB (NF-kappaB/NF-[kappa]B), Bcl-2 family, and NF-kappaB-dependent antiapoptotic genes (survivin, X-linked inhibitors of apoptosis, and cyclooxygenase-2), thymoquinone could potentiate the killing of pancreatic cancer cells induced by chemotherapeutic agents (gemcitabine and oxaliplatin). Cucurbitacin B, a member of the cucurbitacins, is derived from Cucurbitaceae family "Trichosanthes kirilowii Maximowicz," a plant that has long been used in oriental medicine for its abortifacient, antidiabetic, and antiinflammatory effects. Thoennissen et al. for the first time showed that cucurbitacin B has profound antiproliferative effects against human pancreatic cancer cells in vitro and in vivo and cucurbitacin B may potentate the antiproliferative activity of nucleoside analogue gemcitabine, associated with inhibition of activated JAK2/STAT3 and decrease of expression of Bcl-XL with subsequent upregulation of caspase3 and caspase-9 [15]. Isothiocyanate sulforaphane (SF) is a natural compound present in broccoli and other cruciferous vegetables with high concentration. Kallifatidis et al. showed that SF increased the effectiveness of cytotoxic drugs (gemcitabine, cisplatin, 5-fluorouracil, and doxorubicin) against pancreatic cancer stem cells (CSCs) without inducing additional toxicity in mice [16]. Combination of SF with cytotoxic drugs intensified inhibition of spheroid formation, clonogenicity, and aldehyde dehydrogenase 1 activity along with the expression of c-Rel and Notch-1, which indicated that the characteristics of CSCs were targeted. Dimethylamino parthenolide (DMAPT) is a sesquiterpene lactone extracted from the medicinal herb feverfew (Tanacetum parthenium). In association with the suppression of NF-[kappa]B, Holcomb et al. indicated that DMAPT enhanced the antiproliferative effects of gemcitabine in pancreatic cancer cells in vitro and in vivo, which supported the evaluation of NF-[kappa]B-targeted agents to complement gemcitabine-based therapies [17]. Dimethylaminoparthenolide (DMAPT) is a novel orally bioavailable analog of parthenolide, a sesquiterpene lactone extracted from the medicinal herb feverfew (Tanacetum parthenium). Yip-Schneider et al. showed that the combination of DMAPT and gemcitabine significantly decreased the multiplicity and incidence of pancreatic adenocarcinomas by reducing the levels of eotaxin, tumor necrosis factoralpha (TNF-[alpha]), macrophage inflammatory protein-1 beta (MIP-1[beta]), inflammatory cytokines IL-12p40, and monocyte chemotactic protein-1 (MCP-1), all of which are NF-[kappa]B target genes [18]. Yip-Schneider et al. also indicated DMAPT and sulindac (nonselective COX inhibitor) in combination with gemcitabine may prevent or delay the progression of premalignant pancreatic lesions in the LSL-Kras (G12D), Pdx-1-Cre mouse model of pancreatic cancer [55]. The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), is a major active ingredient extracted from the seed oil of Croton tiglium L., a leafy shrub of the Euphorbiaceae family which is native to Southeastern Asia. Our laboratory indicated that the combination of TPA with gemcitabine synergistically inhibited growth and induced apoptosis in human pancreatic cancer PANC-1 cells cultured in vitro or PANC-1 cells grown in NCr immunodeficient nude mice [19]. 0.16 nM TPA in combination with 0.5 [micro]M gemcitabine induced a remarkable increase in the expression of phosphorylated c-Jun NH2-terminal kinase (JNK) in PANC-1 cells. Guggulsterone (4,17[20]-pregnadiene-3,16-dione) is a dietary plant sterone obtained from the gum resin of the Indian Ayurvedic medicinal plant, Commiphora mukul, which has been used as traditional medicine since 600 BC. It has been known to show hypolipidemic activity, cardiovascular protecting activity, anti-inflammatory activity, and the activity of antagonist to bile acid receptor (farnesoid X receptor) [56]. Ahn et al. indicated that guggulsterone combined with gemcitabine augmented growth inhibition of pancreatic cancer cells in vitro and in vivo through downregulation of nuclear factor-[kappa]B activity, suppression of BcL-2 and Akt expression, and activation of Bax and c-Jun NH(2)-terminal kinase [20]. Akasaka et al. indicated that monogalactosyl diacylglycerol (MGDG), a glycoglycerolipid isolated from spinach, combined with gemcitabine revealed synergistic effects of inhibitive proliferation on human pancreatic cancer cell lines BxPC-3, MiaPaCa2, and PANC-1 through the inhibition of DNA replicative pols alpha and gamma activities, compared with MGDG or GEM alone [21]. Glaucarubinone, a quassinoid natural product, was first extracted from the seeds of Simarouba glauca and numerous other species in the family Simaroubaceae. Yeo et al. indicated glaucarubinone and gemcitabine synergistically reduced the growth of pancreatic cancer cells in vitro and in vivo via downregulation of P21-activated serine/threonine kinases PAK1 and PAK4 [22]. Thymoquinone is a bioactive constituent isolated from the volatile oil of the black seed (Nigella sativa). Mu et al. showed thymoquinone pretreatment following gemcitabine treatment synergistically caused an increase of apoptosis and tumor growth inhibition in pancreatic cancer cells both in vitro and in vivo, through abrogation of Notch1, PI3K/Akt/mTOR regulated signaling pathways [23]. Namba et al. indicated zidovudine, developed from spongothymidine extracted from Cryptotethya crypta, resensitized gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibiting the Akt-GSK3[beta]-Snail pathway [24]. Piperlongumine is a natural alkaloid/amide component extracted from the fruit of the pepper Piper longum. Wang et al. indicated that Piperlongumine enhanced the antitumor properties of gemcitabine in human pancreatic cancer cells in vitro and in vivo by modulating the NF-kappaB pathway [25].

Escin is a natural mixture of pentacyclic triterpene saponins extracted from the horse chestnut (Aesculus hippocastanum/Aesculus wilsonii Rehd.) seeds that has been used as an antipyretic and an analgesic agent in China. It possesses anticancer activity by induction of growth inhibition and apoptosis in many human cancer cells. Wang et al. showed escin could potentiate the efficacy of gemcitabine against human pancreatic cancer in vitro and in vivo via inactivation of NF-[kappa]B and consequent inhibition of c-Myc, Bcl-2, Bcl-xL, survivin, COX-2, cyclin D1, and the activation of caspase-3 [26]. Rimmon et al. indicated that the combination of escin with gemcitabine showed only additive effect in pancreatic cancer PANC-1 cells, while escin combined with cisplatin led to a significant synergistic cytotoxic effect in PANC-1 cells by downregulating NF-[kappa]B signaling pathway [27]. Gum mastic, a natural resin isolated from the leaves and stem of Pistacia lentiscus trees, has been extensively used as both an herbal remedy and a dietary supplement for centuries in Mediterranean and Middle Eastern countries. Huang et al. indicated gum mastic significantly potentiated antiproliferative and apoptotic effects of gemcitabine in both pancreatic cancer BxPC-3 and COLO 357 cells by increasing the expression of IkappaBalpha and Bax protein, blocking NF-kappaB activation and downregulating the expression of Bcl-2 protein [28]. Zyflamend is a polyherbal formulation comprised of ten standardized and concentrated herbal extracts (ginger, holy basil, rosemary, huzhang, oregano, turmeric, Chinese goldthread, baikal skullcap, barberry, and green tea). Kunnumakkara et al. showed Zyflamend in combination with gemcitabine synergically inhibited the growth of human pancreatic cells in vitro and in vivo by inhibiting NF-[kappa]B signaling pathways [29]. MK615, called Ume in Japanese, is a sticky extract from Japanese apricot, which has been used to treat intestinal disorders for many years as an antipyretic and an anti-inflammatory agent [57]. Hattori et al. indicated MK615, in both the presence and absence of gemcitabine, significantly inhibited the growth of human pancreatic cancer cells in vitro and in vivo without apparent adverse effects through a reactive oxygen species-dependent mechanism [30]. Herbal preparation of Pao Pereira, obtained from a rainforest tree in the family of Apocynaceae, has long been used by practitioners and oncologic patients in complementary and alternative medicine. Yu et al. showed the combination of the extract of Pao Pereira and gemcitabine had a synergistic effect in inhibiting growth and inducing apoptosis of pancreatic cancer cells [31]. Qingyihuaji formula (QYHJ), consisting of traditional Chinese herbs, has been used for integrative treatment of human pancreatic cancer in China for many years. Xu et al. indicated that QYHJ could enhance the antitumor activity of gemcitabine pancreatic cancer cells by downregulating the expression of Jagged-1 and Notch-4 in Notch signaling pathway [32]. Pan et al. indicated that PBI-05204, a modified supercritical C[O.sub.2] extract of Nerium oleander, markedly enhanced the antitumor efficacy of gemcitabine in a human pancreatic cancer PANC-1 orthotopic model and human pancreatic cancer cell lines, through downregulation of PI3k/Akt and mTOR pathways [33].

Devil's club Oplopanax horridus (DC), an important medicinal herb of the Pacific Northwest, is a deciduous shrub related in taxonomy to the well-known medicinal plants such as Asian ginseng (Panax ginseng C. A. Meyer), American ginseng (Panax quinquefolius L.), and eleuthero (Eleutherococcus senticosus Maxim. or Acanthopanax senticosus, formerly known as Siberian ginseng). The inner root and stem bark extract of DC show antiproliferation activity on multiple cancer cells in vitro. Tai et al. indicated that there was a significant antiproliferation activity of DC extract alone or in combination with chemotherapeutic agents (gemcitabine, cisplatin, and paclitaxel) on human pancreatic cancer PANC-1 3D spheroids and 2D monolayer cells [34]. Cheung et al. also indicated that DC 70% ethanol extract alone or in combination with chemotherapeutic agents (gemcitabine, cisplatin, and paclitaxel) displayed the high antiproliferation potency on pancreatic endocrine HP62 cells and pancreatic ductal carcinoma BxPC-3 and PANC-1 cells [35]. Summary of pharmacological studies of combination of natural products with gemcitabine was shown in Table 1.

3. Combination of Natural Products with Other Chemotherapeutic Agents

Our laboratory indicated that the combination of 12-O-tetradecanoylphorbol-13- acetate (TPA) with All-trans Retinoic Acid (ATRA) synergistically inhibited growth and increased apoptosis in human pancreas cancer cells cultured in vitro or pancreas tumor xenografts in immunodeficient mice [36]. The combination of TPA and ATRA induced a remarkable decrease ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. Our laboratory showed that the combination of TPA and diethyldithiocarbamate (DDTC) synergistically inhibited growth and increased apoptosis in human pancreas cancer cells cultured in vitro and pancreas tumor xenografts in nude mice [37]. The combination of TPA and DDTC induced a remarkable inhibition on the activation of nuclear factor-[kappa]B (NF-[kappa]B) and decreased the expression of Bcl-2. Parthenolide is a sesquiterpene lactone extracted from the medicinal herb feverfew (Tanacetum parthenium). Yip-Schneider et al. showed that the combination of nonsteroidal anti-inflammatory drug sulindac with parthenolide inhibited cell growth additively in pancreatic cancer PANC-1 cells and synergistically in pancreatic cancer BxPC-3 and MiaPaCa-2 cells, by increasing the expression level of IkappaBalpha protein and decreasing the binding and transcriptional activities of NF-kappaB DNA [38]. Yip-Schneider et al. also indicated that the combination of the cyclooxygenase 2 inhibitor celecoxib with dimethylaminoparthenolide exhibited significant inhibitory effect of tumor invasion into adjacent organs and metastasis in a carcinogen-induced pancreatic cancer model of Syrian golden hamsters, by decreasing the activity of nuclear factor-kappaB and the expression of prostaglandin E2 and prostaglandin E2 metabolite [39]. Yang et al. indicated that triptolide in combination with hydroxycamptothecin displayed the synergistic cytotoxic effect on pancreatic cancer PANC-1 cells [40]. Sulforaphane, derived from glucoraphanin, was a major glucosinolate and a dietary component in broccoli and broccoli sprouts. Li et al. indicated that the combination of sulforaphane with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin synergistically inhibited cell growth in vitro and in pancreatic cancer xenograft model in vivo, by decreasing the function of Hsp90 and increasing the activity of caspase-3 [41]. Yuan et al. indicated that the combination of small-molecule BRD4770 (an histone methyltransferase G9a inhibitor) with gossypol (a natural product isolated from cottonseeds) synergistically enhanced the cytotoxicity of p53-mutant pancreatic cancer PANC-1 cells but there was no effect in immortalized nontumorigenic pancreatic cells [42]. The combination of gossypol and BRD4770 induced autophagy-related cell death in pancreatic cancer cells by increasing the levels of LC3-II and the number of autophagosome.

SPES contains 15 herbs: Cervus nippon, Pyrola rotundifolia, Panax ginseng, Ganoderma japonicum, Agrimonia pilosa, Cistanche deserticola, Corydalis bulbosa, Pollen, Glycyrrhiza glabra, Stephania delavayi, Lycoris radiata, Stephania sinica, Zanthoxylum nitidum, Rabdosia rubescens, and Patrinia heterophylla. PC-SPES consists of powders derived from 8 herbs: Dendranthema morifolium, Isatis indigotica, Panax ginseng, Ganoderma lucidum, Serenoa repens, Scutellaria baicalensis, Rabdosia rubescens, and Glycyrrhiza glabra. Schwarz et al. evaluated the antitumor effects of Chinese herbs (SPES and PC-SPES) combined with the chemotherapeutic drugs (doxorubicin or gemcitabine) on eight human pancreatic cancer cell lines (CFPAC, BxPC, MIA, HS-766T, PANC-1, HTB-147, CaPan-2, and ASPC) in vitro [43]. Mediated via induction of apoptosis, both SPES and PC-SPES exhibited significant inhibitory effect on pancreatic cancer cells. Combination effects with either extract appeared to be additive to mildly synergistic in the case of gemcitabine while they appeared to be antagonistic in the case of doxorubicin. Berberis vulgaris, which belongs to Berberidaceae family, is a plant growing in Asia and Europe. Berberis extract has been used for a long time in folk medicine, whose therapeutic value is attributed to the fruits, leaves, bark, and root. Berberine is the most potent of these alkaloids extracted from Berberis vulgaris, responsible for the majority of pleiotropic effects against a number of cancer cell lines. Issat et al. showed cholesterol-reducing agents lovastatin in combination with berberine exert potentiated cytotoxic and/or cytostatic effects against murine Panc 02 pancreatic cancer cells and human MDA-MB231 breast cancer cells [58]. Cell cycle was inhibited in G1 phase after 48 h of incubation with lovastatin and berberine. The combination of lovastatin and berberine slightly, but significantly, decreased tumor growth in a Panc 02 pancreatic cancer model of mice. Moringa oleifera Lam. (Moringaceae) is a tree that grows widely in the tropics and subtropics of Asia and Africa. Leaves of Moringa oleifera consist of flavonoid pigments, such as kaempferitrin, kaempferol, isoquercitrin, and rhamnetin. Berkovich et al. indicated that Moringa oleifera leaf extract synergistically inhibited tumor growth and enhanced the cytotoxic effect of cisplatin in human pancreas cancer PANC-1 cells in vitro, by elevating the sub-G1 cell population of cell cycle and reducing the expression of p65, p-IkB[alpha], and IkB[alpha] proteins [44]. Reis et al. indicated that the combination of lathyranes, the chemical compound isolated from Euphorbia piscatoria, and doxorubicin synergistically enhanced the antiproliferative activity on human pancreatic cells in vitro [59]. Summary of pharmacological studies of combination of natural products with other chemotherapeutic agents was shown in Table 2.

4. Combination between Natural Products

Mohammad et al. showed that the combination of (-)-gossypol (a natural polyphenolic compound extracted from cotton seeds) with genistein (a prominent soy isoflavone) more significantly inhibited the growth of BxPC-3 pancreatic cancer cells, compared with either agent alone. Genistein, which inactivated NF-[kappa]B and caused transcriptional inactivation of Bcl-XL and Bcl-2, could be combined with (-)-gossypol to inactivate the function of Bcl-XL and Bcl-2 and then enhanced the death of pancreatic cancer cells [45]. Srivastava et al. indicated that sulforaphane, an active compound in cruciferous vegetables, synergistically inhibits self-renewal capacity of pancreatic cancer stem cells with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables, by inhibiting the expression of Nanog, phosphorylation of FKHR, Bcl-2, XIAP, activating caspase-3, and proteins involved in the epithelial-mesenchymal transition (beta-catenin, twist-1, ZEB1, and vimentin) [46]. Ding et al. showed the combination of that wogonin, a naturally occurring flavone, with the structurally related natural flavones apigenin and chrysin could enhance TRAIL-mediated apoptosis in pancreatic carcinoma CaPan-1 cells, by upregulation of TRAIL receptor 2 (TRAIL-R2) and transcriptional downregulation of c-FLIP (a key inhibitor of death receptor signaling) [47]. Yue et al. indicated that metformin combined with aspirin synergistically inhibited tumor growth, migration, and colony formation in human pancreas cancer PANC-1 and BxPC-3 cells cultured in vitro and pancreas tumor xenografts in nude mice, by remarkably inhibiting the phosphorylation of STAT3 and mTOR, significantly downregulating the antiapoptotic proteins Bcl-2 and Mcl1 and significantly upregulating the proapoptotic proteins Puma and Bim [48]. Summary of pharmacological studies of combination between natural products was shown in Table 3.

5. Combination of Natural Products in Early Phases of Clinical Trials

Hauns et al. indicated that Ginkgo biloba extract GBE 761 ONC combined with 5-fluorouracil (5-FU) was shown favourable effect to treat the patients with pancreatic cancer in the clinical trial phase II study, compared to the clinical trial of 5-FU monotherapy [60]. Curcumin, which is called diferuloyl methane, is a hydrophobic polyphenol isolated from rhizome (turmeric) of the herb Curcuma longa. Curcumin has shown various activities, such as a mediator of chemoresistance and radio-resistance, antioxidant, antiinflammatory, and immunomodulatory activities, enhancing of the apoptotic process, cytokines release, and antiangiogenic properties. The anticancer effect has been seen in a few clinical trials, mainly as a native chemoprevention agent in colon and pancreatic cancer, cervical neoplasia, and Barrett's metaplasia [61]. Although curcumin may potentiate the antitumor effect of gemcitabine by intervening with several intracellular signal transduction pathways in pancreatic cancer cells in vitro and in vivo, Epelbaum et al. showed that a combination of gemcitabine and oral curcumin at a dose of 8,000 mg/day to treat the patients with advanced pancreatic cancer is not feasible and 29% patients had to stop oral curcumin due to gastrointestinal toxicity [62]. The preliminary results suggest that a combination of curcumin and gemcitabine for the patients with advanced pancreatic cancer is feasible. Mistletoe extracts from the medicinal herb Viscum album L. are widely used to treat cancer patients in Europe. Matthes et al. indicated that mistletoe extract (Iscador[R], Weleda, Arlesheim, Switzerland) could be supportive care in an adjuvant chemotherapy setting with gemcitabine or 5-fluorouracil (5-FU) in the patients undergoing curative intent resection of pancreatic cancer [63]. Lohr et al. reported the phase Ib study of 16 chemotherapy-native patients with inoperable pancreatic carcinoma treated with gemcitabine and AXP107-11, the sodium salt dihydrate form of genistein (genistein-SSDH, a novel multicomponent crystalline form of genistein) [64]. The results demonstrated that treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine led to a favorable pharmacokinetics with high serum levels without toxicity.

Traditional Chinese herbal formulation Huang-Qin-Tang (HQT), which had been documented for almost 1800 years to treat common gastrointestinal distress, such as diarrhea, headache, abdominal spasms, nausea, fever, subcardiac distention, extreme thirst, and vomiting, included four distinct herbs: the roots of Scutellaria baicalensis Georgi. (scute), Glycyrrhiza uralensis Fisch. (licorice), and Paeonia lactiflora Pall. (peony) and the fruit of Ziziphus jujuba Mill. (Chinese date). Each herb of Huang-Qin-Tang had an unusual pharmacological profile, which was involved in antiviral and anticancer activity, liver protection, hematological and immunological modulation, appetite improvement, and analgesic activity. Botanical formulation PHY906, a pharmaceutical grade of Huang-Qin-Tang, was explored as an adjuvant for chemotherapy and targeted therapy of tumors by the teams led by Professor Yung-Chi Cheng in Yale University School of Medicine and PhytoCeutica, Inc. PHY906 was distinguished from Huang-Qin-Tang which is currently available in the market, due to the unique and defined procedures for its characterization, preparation, and quality control. An open label phase I/II study of PHY906 in combination with capecitabine in the patients with advanced pancreatic was concluded at Yale Cancer Center in 2009. Saif et al. conducted phase I study in the patients with advanced pancreatic and gastrointestinal malignancies using PHY906 combined with capecitabine to determine the maximum tolerated dose (MTD) of capecitabine in combination with PHY906 [65]. The results of phase I study indicated that the MTD of capecitabine was 1500 mg/m2 BID administered in a 7/7 schedule, combined with PHY906 800 mg BID on days 1-4. Saif et al. also carried out phase II study in the patients with advanced pancreatic cancer who were previously treated with gemcitabine-based regimens to explore the efficacy of capecitabine in combination with PHY906 [66]. The results of phase II study showed that capecitabine combined with PHY906 displayed a feasible and safe salvage therapy after the failure of gemcitabine for advanced pancreatic cancer.

6. Conclusions and Future Directions

Although there are great improvements in the treatment of many common cancers in clinic (e.g., prostate cancer and breast cancer) in recent decades, pancreatic cancer still remains the most deadly diagnosed cancer and represents a major challenge [10]. Herbal remedies have been used to treat various diseases for thousands of years in numerous countries, such as China, Egypt, Japan, and Korea, which have come to be accepted as forms of complementary and alternative medicines in western countries [67]. Therefore, natural products/herbal medicines play important roles in prevention and therapy of pancreatic cancer as a promising adjunctive approach. They have been credited with substantial advantages, including improving immune system, suppressing tumor progression, enhancing beneficial effects, and lessening adverse/side effects of chemotherapy and radiotherapy [11]. Unlike western medicine which generally uses purified chemical compounds and targets single physiological endpoints, natural products/herbal medicines usually consist of multiple components and herbs which act/interact simultaneously through various cellular signal mechanisms and molecular targets [10]. These multiple herbs serve various functions; some may improve the efficacy while others may increase the bioavailability or decrease the toxicity. Even isolated compounds from natural products/herbal medicines may display multiple effects, such as improving the efficacy and decreasing the toxicity of chemotherapy and/or radiotherapy. So, there are various natural products/herbal medicines targeting multiple cancer-related proteins and pathways, which make them an attractive direction as supplementary therapeutics for the patients with pancreatic cancer [11].

Herbal medicine formulations, including Chinese herbal medicine, have been originated from empirical observations in humans over thousands of years. As a complementary and alternative therapy, Chinese herbal medicine has increasingly drawn an interest among international cancer research studies because it can increase the efficacy and decrease the toxicity when combined with chemotherapy and/or radiotherapy. Moreover, according to NCCN clinical practice guidelines, the integration of palliative care in cancer patients has become standard oncology practice when a patient is diagnosed with metastatic or advanced cancer, including pancreatic cancer [12]. Chinese herbal medicine has a longstanding history in China and it is deeply embedded in urban and rural populations as a measure of palliative care. The phenomena are attributed to the fact that the origin and the development of traditional Chinese medicine are intricately entwined with Chinese history, economy, politics, and culture, whose compelling efficacy has been attested. Though Chinese herbal medicine has multiple complicated components and probable adverse effects, its application has been widely embraced in clinical practice, especially throughout China. Chinese herbal medicine has also been accepted into Chinese clinical practice guidelines to treat pancreatic cancers [12]. Preclinical studies have demonstrated that Chinese herbal medicine can suppress tumor proliferation and metastasis. Recent reported studies have shown that 90% Chinese patients with cancer are treated with diverse Chinese herbal medicine alone or in combination with chemotherapy and/or radiotherapy during their treatment regimen [12]. Chinese herbal medicine can increase the effect of antitumor therapies and improve the quality of life or the performance status of pancreatic cancer patients, which will provide more evidence to promote the application of Chinese herbal medicine to benefit the patients with pancreatic cancer in the world.

http://dx.doi.org/10.1155/2017/8412508

Competing Interests

The authors confirmed that this article content has no conflict of interests. The authors declared no potential conflict of interests with respect to the research, authorship, and/or publication of this article.

Authors' Contributions

Qingxi Yue and Guogang Gao contributed equally to this work.

Acknowledgments

This work was supported in part by grants from National Nature Science Foundation (81302809 and 81272452), Research Program of Shanghai Municipal Commission of Health and Family Planning (20154Y0149), fund of Shanghai Jiaotong University (syzrc2014-001, syz2014-005, and YG2015MS24), and National Cancer Institute Foundation (P30-CA072720). The authors would like to thank Scientific Creation (Shanghai) Bio-Tech Co. Limited for technology support and helpful advice.

References

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Qingxi Yue, (1, 2) Guogang Gao, (3) Gangyong Zou, (4) Haiqing Yu, (5) and Xi Zheng (2, 6)

(1) Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

(2) Department of Chemical Biology Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey Piscataway, NJ, USA

(3) Department of Cardiothoracic Surgery, Weihai Municipal Hospital, Weihai, Shandong, China

(4) Department of Pathology, Weihai Municipal Hospital, Weihai, Shandong, China

(5) Department of Internal Medicine, University of Missouri Hospital and Clinics, Columbia, MO, USA

(6) Allan H. Conney Laboratory for Anticancer Research, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, China

Correspondence should be addressed to Qingxi Yue; qxyue@sibs.ac.cn and Xi Zheng; xizheng@pharmacy.rutgers.edu

Received 3 August 2016; Revised 9 December 2016; Accepted 27 December 2016; Published 23 January 2017

Academic Editor: Li Jiao
Table 1: Summary of pharmacological studies of combination
of natural products with gemcitabine.

Combination of               Experimental model
natural products
with gemcitabine

Combination of 3,3-          PANC-1 Panc-28, and
diindolylmethane             Colo-357 pancreatic
with gemcitabine             cancer cells (in
                             vitro); PANC-1
                             pancreatic cancer
                             cells orthotopic
                             xenografts (in vivo)

Combination of               BxPC-3 and HPAC
thymoquinone with            pancreatic cancer
gemcitabine                  cells (in vitro);
                             HPAC pancreatic
                             cancer cells
                             orthotopic
                             xenografts (in vivo)

Combination of               MiaPaCa-2, PL45,
cucurbitacin B with          PANC-1, SU86.86,
gemcitabine                  AsPC-1, Panc-03.27,
                             and Panc-10.05
                             pancreatic cancer
                             cells (in vitro);
                             PANC-1 pancreatic
                             cancer cells
                             xenografts (in vivo)

Combination of               MIA-PaCa2 pancreatic
sulforaphane with            cancer cells (in
gemcitabine                  vitro); MIA-PaCa2
                             pancreatic cancer
                             cells xenografts (in
                             vivo)

Combination of               BxPC-3, PANC-1, and
dimethylamino-               MiaPaCa-2 pancreatic
parthenolide                 cancer cells (in
with gemcitabine             vitro); MiaPaCa-2
                             pancreatic cancer
                             cells heterotopic
                             xenograft (in vivo)

Combination of               MiaPaCa pancreatic
dimethylamino-               cancer cells (in
parthenolide                 vitro); MiaPaCa
with gemcitabine             pancreatic cancer
                             cells xenografts (in
                             vivo)

Combination of 12-           PANC-1 pancreatic
O-                           cancer cells (in
tetradecanoylphorbol-        vitro); PANC-1
13-acetate with              tumors grown in
gemcitabine                  immunodeficient mice
                             (in vivo)

Combination of               MiaPaCa-2 and Panc-
guggulsterone with           1 pancreatic cancer
gemcitabine                  cells (in vitro);
                             MiaPaCa-2 pancreatic
                             cancer cells
                             xenografts (in vivo)

Combination of               BxPC-3, MiaPaCa2 and
monogalactosyl               PANC-1 pancreatic
diacylglycerol with          cancer cells (in
gemcitabine                  vitro)

Combination of               PANC-1, MiaPaCa-2,
glaucarubinone with          and PAN02 pancreatic
gemcitabine                  cancer cells (in
                             vitro); PANC-1 and
                             MiaPaCa-2 pancreatic
                             cancer cells
                             xenograft (in vivo)

Combination of               PANC-1, BxPC-3, and
thymoquinone with            AsPC-1 pancreatic
gemcitabine                  cancer cells (in
                             vitro); PANC-1
                             pancreatic cancer
                             cells orthotopic
                             xenograft (in vivo)

Combination of               PK1 and KLM1
Zidovudine with              pancreatic cancer
gemcitabine                  cells (in vitro);
                             PK1 and KLM1
                             pancreatic cancer
                             cells xenografts (in
                             vivo)

Combination of               PANC-1, BxPC-3, and
piperlongumine with          AsPC-1 pancreatic
gemcitabine                  cancer cells (in
                             vitro); BxPC-3
                             pancreatic cancer
                             cells xenografts (in
                             vivo)

Combination of escin         BxPC/3 and PANC/1
with gemcitabine             pancreatic cancer
                             cells (in vitro);
                             BxPC/3 pancreatic
                             cancer cells
                             xenografts
                             subcutaneously
                             established in BALB/
                             c nude mice (in
                             vivo)

Combination of escin         PANC-1 pancreatic
with gemcitabine             cancer cells (in
                             vitro)

Combination of gum           BxPC-3 and COLO 357
mastic with                  pancreatic cancer
gemcitabine                  cells (in vitro)

Combination of               AsPC-1, BxPC-3,
Zyflamend with               MiaPaCa-2, and PANC-
gemcitabine                  1 pancreatic cancer
                             cells (in vitro);
                             MiaPaCa-2 pancreatic
                             cancer cells
                             orthotopic
                             xenografts (in vivo)

Combination of               MiaPaCa-2 pancreatic
Japanese apricot             cancer cells (in
extract (MK615) with         vitro); MiaPaCa-2
gemcitabine                  pancreatic cancer
                             cells xenografts (in
                             vivo)

Combination of the           PANC-1, AsPC-1,
extract of Pao               HPAF-II, BxPC-3, and
Pereira with                 MiaPaCa-2 pancreatic
gemcitabine                  cancer cells (in
                             vitro); PACN-1
                             pancreatic cancer
                             cells xenografts (in
                             vivo)

Combination of               SW1990 pancreatic
Qingyihuaji formula          cancer cells (in
with gemcitabine             vitro); SW1990
                             pancreatic cancer
                             cells xenografts (in
                             vivo)

Combination of PBI-          PANC-1 pancreatic
05204 (a                     cancer cells (in
supercritical C[O.sub.2]     vitro); PANC-1
extract of Nerium            pancreatic cancer
oleander containing          orthotopic model (in
oleandrin) with              vivo)
gemcitabine

Combination of               PANC-1 pancreatic
Devil's club                 cancer cells (in
Oplopanax horridus           vitro)
with gemcitabine

Combination of               PANC-1 and BxPC-3
Devil's club                 pancreatic cancer
Oplopanax horridus           cells (in vitro)
with gemcitabine

Combination of               Anticancer/
natural products             anticarcinogenic
with gemcitabine             effects

Combination of 3,3-          Reduced the
diindolylmethane             proliferation of
with gemcitabine             pancreatic cancer
                             cells

Combination of               Reduced the
thymoquinone with            proliferation of
gemcitabine                  pancreatic cancer
                             cells

Combination of               Synergistically
cucurbitacin B with          potentiated the
gemcitabine                  antiproliferative
                             effects of
                             pancreatic cancer
                             cells

Combination of               Enhanced additive
sulforaphane with            cytotoxic effect to
gemcitabine                  pancreatic cancer
                             cells

Combination of               Synergistically
dimethylamino-               inhibited the
parthenolide                 proliferation of
with gemcitabine             pancreatic cancer
                             cells

Combination of               Synergistically
dimethylamino-               inhibited the
parthenolide                 proliferation of
with gemcitabine             pancreatic cancer
                             cells

Combination of 12-           Synergistically
O-                           inhibited the growth
tetradecanoylphorbol-        and induced
13-acetate with              apoptosis in PANC-1
gemcitabine                  cells

Combination of               Synergistically
guggulsterone with           enhanced antitumor
gemcitabine                  efficacy of
                             pancreatic cancer
                             cells through
                             apoptosis induction

Combination of               Synergistically
monogalactosyl               enhanced the growth
diacylglycerol with          suppression of
gemcitabine                  pancreatic cancer
                             cells

Combination of               Inhibited the growth
glaucarubinone with          of pancreatic cancer
gemcitabine                  cells

Combination of               Synergistically
thymoquinone with            caused an increase
gemcitabine                  in pancreatic cancer
                             cells apoptosis and
                             tumor growth
                             inhibition both in
                             vitro and in vivo

Combination of               Resensitized
Zidovudine with              gemcitabine-
gemcitabine                  resistant pancreatic
                             cancer cells to
                             gemcitabine

Combination of               Synergistically
piperlongumine with          inhibited the
gemcitabine                  proliferation of
                             pancreatic cancer
                             cells

Combination of escin         Dramatically
with gemcitabine             enhanced the
                             suppressive effect
                             of pancreatic cancer
                             cells

Combination of escin         Enhanced additive
with gemcitabine             cytotoxic effect to
                             pancreatic cancer
                             cells

Combination of gum           Enhanced
mastic with                  antiproliferative
gemcitabine                  and apoptotic
                             effects of
                             pancreatic cancer
                             cells

Combination of               Inhibited the growth
Zyflamend with               of human pancreatic
gemcitabine                  tumors and
                             sensitized
                             pancreatic cancer to
                             gemcitabine

Combination of               Significantly
Japanese apricot             inhibited the growth
extract (MK615) with         of human pancreatic
gemcitabine                  cancer cells

Combination of the           Enhanced the
extract of Pao               inhibitory effect of
Pereira with                 pancreatic cancer
gemcitabine                  cells

Combination of               Enhanced the
Qingyihuaji formula          antitumor activity
with gemcitabine             of gemcitabine to
                             pancreatic cancer
                             cells

Combination of PBI-          Markedly enhanced
05204 (a                     the antitumor
supercritical C[O.sub.2]     efficacy of
extract of Nerium            gemcitabine to
oleander containing          pancreatic cancer
oleandrin) with              cells
gemcitabine

Combination of               Significantly
Devil's club                 enhanced the
Oplopanax horridus           antiproliferation
with gemcitabine             activity of
                             gemcitabine to
                             pancreatic cancer
                             cells

Combination of               Significantly
Devil's club                 enhanced the
Oplopanax horridus           antiproliferation
with gemcitabine             activity of
                             gemcitabine to
                             pancreatic cancer
                             cells

Combination of                Mechanism of action     Reference
natural products                 ([down arrow]
with gemcitabine              downregulated) ([up
                              arrow] upregulated)

Combination of 3,3-            NF-[kappa]B [down         [13]
diindolylmethane              arrow], phospho-p65
with gemcitabine               [down arrow], Bcl-
                                xL [down arrow],
                               XIAP [down arrow],
                               XIAP [down arrow],
                                 survivin [down
                                  arrow], PARP
                              cleavage [up arrow]

Combination of                 NF-[kappa]B [down         [14]
thymoquinone with             arrow], Bcl-2 family
gemcitabine                    [down arrow], XIAP
                                 [down arrow],
                                 survivin [down
                              arrow], COX-2 [down
                                    arrow]

Combination of                 JAK2 [down arrow],        [15]
cucurbitacin B with           STAT3 [down arrow],
gemcitabine                   STAT5 [down arrow],
                                 cyclin A [down
                               arrow], cyclin B1
                               [down arrow], Bcl-
                                XL [down arrow],
                                 p21(WAF1) [up
                                arrow], p53 [up
                               arrow], caspase-3
                              [up arrow], caspase-
                                 9 [up arrow]

Combination of                ALDH1 [down arrow]         [16]
sulforaphane with
gemcitabine

Combination of                 NF-[kappa]B [down         [17]
dimethylamino-                      arrow],
parthenolide                  I[kappa]B[alpha] [up
with gemcitabine                    arrow]

Combination of                   IL-12p40 [down          [18]
dimethylamino-                arrow], MCP-1 [down
parthenolide                  arrow], MIP-1[beta]
with gemcitabine                 [down arrow],
                                 eotaxin [down
                              arrow], TNF-[alpha]
                                 [down arrow]

Combination of 12-              JNK [up arrow]           [19]
O-
tetradecanoylphorbol-
13-acetate with
gemcitabine

Combination of                 NF-[kappa]B [down         [20]
guggulsterone with             arrow], Akt [down
gemcitabine                   arrow], BcL-2 [down
                               arrow], c-Jun [up
                                arrow], Bax [up
                                    arrow]

Combination of                   Mammalian pol           [21]
monogalactosyl                   [alpha] [down
diacylglycerol with             arrow], [gamma]
gemcitabine                      [down arrow],
                              [delta] [down arrow]
                              and [epsilon] [down
                                    arrow]

Combination of                 PAK1 [down arrow],        [22]
glaucarubinone with            PAK4 [down arrow]
gemcitabine

Combination of                Notch1 [down arrow],       [23]
thymoquinone with              NICD [down arrow],
gemcitabine                   PTEN [up arrow], p-
                               p65 [down arrow],
                              Bcl-2 [down arrow],
                              Bcl-xL [down arrow],
                               XIAP [down arrow],
                                 caspase-3 [up
                               arrow], caspase-9
                              [up arrow], Bax [up
                              arrow], cytochrome c
                                  [up arrow]

Combination of                hENT1 [down arrow],        [24]
Zidovudine with                EMT-like phenotype
gemcitabine                   [up arrow], the Akt-
                               GSK3[beta]-Snail1
                              pathway [up arrow]

Combination of                 NF-[kappa]B [down         [25]
piperlongumine with           arrow], c-Myc [down
gemcitabine                    arrow], cyclin D1
                              [down arrow], Bcl-2
                               [down arrow], Bcl-
                                xL [down arrow],
                                 survivin [down
                               arrow], XIAP [down
                               arrow], VEGF [down
                              arrow], MMP-9 [down
                               arrow], PCNA [down
                              arrow], Ki-67 [down
                               arrow], CD31 [down
                                    arrow]

Combination of escin           NF-[kappa]B [down         [26]
with gemcitabine              arrow], c-Myc [down
                              arrow], COX-2 [down
                               arrow], Cyclin D1
                                 [down arrow],
                                 Survivin [down
                              arrow], Bcl-2 [down
                              arrow], Bcl-xL [down
                               arrow], caspase-3
                                  [up arrow]

Combination of escin           NF-[kappa]B [down         [27]
with gemcitabine                arrow], cyclin D
                                 [down arrow]

Combination of gum             NF-[kappa]B [down         [28]
mastic with                         arrow],
gemcitabine                   I[kappa]B[alpha] [up
                                arrow], Bax [up
                              arrow], Bcl-2 [down
                                    arrow]

Combination of                 NF-[kappa]B [down         [29]
Zyflamend with                 arrow], cyclin D1
gemcitabine                   [down arrow], c-myc
                              [down arrow], COX-2
                              [down arrow], Bcl-2
                               [down arrow], IAP
                                 [down arrow],
                                 survivin [down
                               arrow], VEGF [down
                              arrow], ICAM-1 [down
                              arrow], CXCR4 [down
                              arrow], Ki-67 [down
                              arrow], COX-2 [down
                              arrow], MMP-9 [down
                                    arrow]

Combination of                 ROS [down arrow]          [30]
Japanese apricot
extract (MK615) with
gemcitabine

Combination of the               Caspase-8 [up           [31]
extract of Pao                 arrow], caspase-3
Pereira with                  [up arrow], PARP [up
gemcitabine                         arrow]

Combination of                   Notch-4 [down           [32]
Qingyihuaji formula             arrow], Jagged-1
with gemcitabine              [down arrow], CD133
                                 [down arrow]

Combination of PBI-           Ki-67 [down arrow],        [33]
05204 (a                       pAkt [down arrow],
supercritical C[O.sub.2]       pS6 [down arrow],
extract of Nerium             p4EPB1 [down arrow]
oleander containing
oleandrin) with
gemcitabine

Combination of                Bcl-2 [down arrow],        [34]
Devil's club                    BAX [up arrow],
Oplopanax horridus            caspase-3 [up arrow]
with gemcitabine

Combination of                  Cytochrome C [up         [35]
Devil's club                  arrow], claspin [up
Oplopanax horridus             arrow], cIAP-2 [up
with gemcitabine                    arrow]

Table 2: Summary of pharmacological studies of combination of
natural products with other chemotherapeutic agents.

Combination of             Experimental model
natural products
with other
chemotherapeutic
agents

Combination of 12-         PANC-1, MiaPaCa-2,
O-                         and BxPC-3
tetradecanoylphorbol-      pancreatic cancer
13-acetate with all-       cells (in vitro);
trans retinoic acid        PANC-1 tumor
                           xenografts in
                           immunodeficient mice
                           (in vivo)

Combination of 12-         PANC-1 pancreatic
O-                         cancer cells (in
tetradecanoylphorbol-      vitro); PANC-1 tumor
13-acetate with            xenografts in nude
diethyldithio carb         mice (in vivo)
am ate

Combination of             BxPC-3, PANC-1, and
parthenolide with          MiaPaCa-2 pancreatic
sulindac                   cancer cells (in
                           vitro)

Combination of             PC-1 pancreatic
celecoxib with             cancer cells
dimethylamino-             xenografts (in vivo)
parthenolide

Combination of             MiaPaCa pancreatic
triptolide with            cancer cells (in
hydroxycamptothecin        vitro); MiaPaCa
                           pancreatic cancer
                           cells xenografts (in
                           vivo)

Combination of             MiaPaCa-2 pancreatic
sulforaphane with          cancer cells (in
17-allylamino 17-          vitro)
demethoxygeldanamycin

Combination of             PANC-1 pancreatic
gossypol with              cancer cells (in
BRD4770 (an HMT G9a        vitro)
inhibitor)

Combination of             MIA, PANC-1, BxPC,
Chinese herbs SPES         ASPC, HS-766T,
with PC-SPES               CaPan-2, CFPAC, and
                           HTB-147 pancreatic
                           cancer cells (in
                           vitro)

Combination of             PANC-1, p34 and COLO
Moringa Oleifera           357 pancreatic
aqueous leaf extract       cancer cells (in
with cisplatin             vitro)

Combination of             Anticancer/
natural products           anticarcinogenic
with other                 effects
chemotherapeutic
agents

Combination of 12-         Enhanced the
O-                         inhibitory effect to
tetradecanoylphorbol-      pancreatic cancer
13-acetate with all-       cells
trans retinoic acid

Combination of 12-         Significantly
O-                         inhibited the growth
tetradecanoylphorbol-      of pancreatic cancer
13-acetate with            cells
diethyldithio carb
am ate

Combination of             Synergistically
parthenolide with          inhibited the growth
sulindac                   of MiaPaCa-2 and
                           BxPC-3 cells and
                           additively inhibited
                           the growth of PANC-
                           1 cells

Combination of             Significantly
celecoxib with             inhibited the growth
dimethylamino-             of pancreatic cancer
parthenolide               cells

Combination of             Enhanced synergistic
triptolide with            cytotoxic effect to
hydroxycamptothecin        pancreatic cancer
                           cells

Combination of             Enhanced the
sulforaphane with          inhibitory effect to
17-allylamino 17-          pancreatic cancer
demethoxygeldanamycin      cells

Combination of             Enhanced the
gossypol with              cytotoxicity to p53-
BRD4770 (an HMT G9a        mutant PANC-1 cells
inhibitor)                 in a synergistic
                           manner

Combination of             Exhibited
Chinese herbs SPES         significant toxicity
with PC-SPES               to pancreatic cancer
                           cells

Combination of             Synergistically
Moringa Oleifera           enhanced the
aqueous leaf extract       cytotoxic effect to
with cisplatin             pancreatic cancer
                           cells

Combination of              Mechanism of action     Reference
natural products               ([down arrow]
with other                  downregulated) ([up
chemotherapeutic            arrow] upregulated)
agents

Combination of 12-            p21 [up arrow],          [36]
O-                          caspase-3 [up arrow]
tetradecanoylphorbol-
13-acetate with all-
trans retinoic acid

Combination of 12-           NF-[kappa]B [down         [37]
O-                          arrow], Bcl-2 [down
tetradecanoylphorbol-             arrow]
13-acetate with
diethyldithio carb
am ate

Combination of               NF-[kappa]B [down         [38]
parthenolide with                 arrow],
sulindac                    I[kappa]B[alpha] [up
                                  arrow]

Combination of               NF-[kappa]B [down         [39]
celecoxib with                    arrow],
dimethylamino-                prostaglandin E2
parthenolide                   [down arrow],
                              prostaglandin E2
                              metabolite [down
                                  arrow]

Combination of               NF-[kappa]B [down         [40]
triptolide with              arrow], caspase-9
hydroxycamptothecin         [up arrow], caspase-
                               3 [up arrow]

Combination of                 Caspase-3 [up           [41]
sulforaphane with           arrow], Hsp90 [down
17-allylamino 17-                 arrow]
demethoxygeldanamycin

Combination of               LC3-II [up arrow],        [42]
gossypol with                autophagosome [up
BRD4770 (an HMT G9a               arrow]
inhibitor)

Combination of                                         [43]
Chinese herbs SPES
with PC-SPES

Combination of              p65 [down arrow], p-       [44]
Moringa Oleifera              IkB[alpha] [down
aqueous leaf extract         arrow], IkB[alpha]
with cisplatin                 [down arrow]

Table 3: Summary of pharmacological studies of combination
between natural products.

Combination between      Experimental model
natural products

Combination of (-)-      BxPC-3 pancreatic
gossypol with            cancer cells (in
genistein                vitro)

Combination of           Pancreatic cancer
sulforaphane with        stem cells (in
quercetin                vitro)

Combination of           CaPan-1 pancreatic
wogonin with             carcinoma cells (in
apigenin and chrysin     vitro)

Combination of           PANC-1 and BxPC3
metformin with           pancreatic carcinoma
aspirin                  cells (in vitro);
                         PANC-1 xenograft
                         mouse model (in
                         vivo)

Combination between      Anticancer/
natural products         anticarcinogenic
                         effects

Combination of (-)-      Significantly
gossypol with            inhibited the growth
genistein                of pancreatic cancer
                         cells

Combination of           Significantly
sulforaphane with        eliminated the
quercetin                growth of pancreatic
                         cancer stem cells

Combination of           Enhanced TRAIL-
wogonin with             mediated apoptosis
apigenin and chrysin     of CaPan-1 human
                         pancreatic carcinoma
                         cells

Combination of           Significantly
metformin with           inhibit the growth
aspirin                  of pancreatic cancer
                         cells

Combination between       Mechanism of action     Reference
natural products

Combination of (-)-            Bcl-XL-Bim            [45]
gossypol with              heterodimerization
genistein                  [down arrow], NF-
                             [kappa]B [down
                          arrow], Bcl-2 [down
                          arrow], Bcl-XL [down
                                arrow]

Combination of            Bcl-2 [down arrow],        [46]
sulforaphane with          XIAP [down arrow],
quercetin                 p-FKHR [down arrow],
                             caspase-3 [up
                             arrow], beta-
                             catenin [down
                            arrow], vimentin
                          [down arrow], twist-
                          1 [down arrow], ZEB1
                             [down arrow]

Combination of            c-FLIP [down arrow],       [47]
wogonin with              p53 [up arrow], Mdm2
apigenin and chrysin      [down arrow], TRAIL-
                             R2 [up arrow]

Combination of            p-mTOR [down arrow],       [48]
metformin with               p-STAT3 [down
aspirin                    arrow], caspase-3
                            [up arrow], PARP
                          cleavage [up arrow],
                          Mcl-1 [down arrow],
                          Bcl-2 [down arrow],
                          Bim [up arrow], Puma
                              [up arrow]
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Article Details
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Author:Yue, Qingxi; Gao, Guogang; Zou, Gangyong; Yu, Haiqing; Zheng, Xi
Publication:BioMed Research International
Article Type:Report
Date:Jan 1, 2017
Words:10273
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