Pancreatic cancer resistance to chemotherapy

CHAPTER 9

Pancreatic cancer resistance to chemotherapy: resensitization strategies using resveratrol Begum Dariya1, Gowru Srivani1, Batoul Farran2, Ramakrishna Vadde3, Afroz Alam1, Ganji Purnachandra 2Nagaraju2 1 Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, India; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States; 3Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India

Abstract Despite tremendous efforts to develop novel therapeutic methods involving chemotherapy and radiotherapy, resistance to chemotherapeutic agents remains a major obstacle in pancreatic cancer (PC). Thus, studies to determine the molecular mechanisms involved in multiple drug resistance are essential for resensitizing tumor cells to therapeutic drugs. Several mechanisms are involved in chemoresistance, including overexpression of signals responsible for cell survival, drug efflux pumps, rapid efficiency in DNA repair, the high toxicity of drugs, and downregulation of apoptotic activity. Phytochemicals including resveratrol (Res), curcumin, and genistein have emerged as potential adjuncts for sensitizing tumor cells to chemotherapeutic agents. For instance, Res can sensitize various tumor cells including prostate cancer, lung carcinoma, multiple myeloma, and PC by modulating multiple signaling pathways including signal transducer and activator of transcription 3, nuclear factor-kb, drug efflux systems, and cell survival proteins involved in developing resistance. This review discusses these various mechanisms of resistance and explores how, with its unique properties, Res is a potential therapeutic agent for PC.

Keywords: Multidrug resistance; Pancreatic cancer; Resveratrol; Sensitized.

Introduction Pancreatic cancer (PC) is the fourth most devastating cancer worldwide and in the United States [1,2]. Statistics have predicted that PC will hold the second place by 2030 [3] because it is asymptomatic in its early stages and symptomatic at its advanced and metastatic stage, which signifies that the therapy depends on the stage. Surgery is the main therapeutic option for PC, followed by chemoradiotherapy. Despite advances in anticancer therapies and the emergence of novel strategies, survival is hindered by G.P. Nagaraju, S. Ahmad (eds.) Theranostic Approach for Pancreatic Cancer ISBN 978-0-12-819457-7 https://doi.org/10.1016/B978-0-12-819457-7.00009-8

Copyright © 2019 Elsevier Inc. All rights reserved.

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acquired and inherent resistance development [4]. Etiological studies reveal that PC growth can be caused by the modern sedentary lifestyle: excess alcohol consumption, smoking, chronic pancreatitis, and long-term diabetes. Furthermore, PC is hereditary and is caused by mutations in genes including SPINK1, CTRC, PRSS1, and PRSS2 [5]. It originates from acinar and ductal cells starting from acinar to ductal metaplasia, owing to a combination of extrinsic factors such as inflammatory damage, oxidative stress, and other genetic alterations in oncogenic KRAS and tumor suppressor genes. There is a strong correlation between PC and diabetes, in which hyperglycemia can cause metastatic PC [6]. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are also considered risk factors, because oxidative stress contributes to the development of PC through pancreatitis and necrosis of cells. Pancreatic stellate cells and endothelial cells generate inflammatory chemokines and cytokines, which together with ROS and RNS can cause damage to epithelial cells and promote the proliferation of PC cells. Cyclooxygenase-2 (COX-2), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kb (NF-kb) also contribute to PC development [7,8]. Moreover, mutations in KRAS induce the detoxification of ROS by activating nuclear factor erythroid 2 (Nrf2), whereas the TP53INP1 protein controls the status of oxidative stress and its inactivation provokes PC growth [9,10]. Hence, these inflammatory pathways and oxidative stress might represent potential therapeutic targets of antiinflammatory and antioxidative agents including phytochemicals such as resveratrol (Res), curcumin, and genistein. Research has also revealed that the microRNA (miRNA) signature of solid cancers including PC differs from that of normal tissue and contributes to tumor development. miRNAs are small fragments of noncoding RNA. They modulate gene expression by targeting mRNA at its 30 untranslated region, thus resulting in the inhibition of translation. Hence, miRNAs are considered a novel avenue of research for cancer biomarkers and drug development and may be promising tools for cancer prognosis and management [11,12]. Bloomston et al. [13], revealed that 21 miRNAs are overexpressed whereas four are downregulated in PC; Zhang et al. [14], found that eight miRNAs (miR-15b, miR-95, miR-190, miR-186, miR-196a, miR-200b, miR-221, and miR-222) are overexpressed in PC. These investigations indicate that miRNAs can have a crucial role in PC proliferation [15]. Studies also revealed that key miRNAs (miR-139, miR-34a, miR-23b, and Let7) and other tumor-suppressive miRNAs are

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downregulated in PC cells. miR-34a, for instance, inhibits tumorigenesis by inducing cell cycle arrest at the G1 and G2/M phase [16]. Moreover, Weiss et al. [17] showed that the overexpression of miR10a contributes to metastasis. In addition to these various alterations that characterize the tumor microenvironment, findings have shown the involvement of cancer stem cells (CSCs) in PC development. CSCs are unique because they can self-renew, undergo symmetric and asymmetric differentiation, and contribute to the development of PC recurrence and metastasis leading to chemoresistance. Because PC prognosis is poor, owing to its delayed diagnosis and rapid progression, and the emergence of multidrug resistance (MDR), novel strategies such as chemosensitization, which uses adjuncts to enhance and potentiate the activity of chemotherapeutics, could aid in overcoming chemoresistance. Hence, naturally available chemosensitizers such as resveratrol (Res), curcumin, genistein, and sulforaphane, which have been used for years, could constitute attractive novel therapeutic options for PC treatment. Furthermore, Res, a phytoalexin characterized by its multitargeting nature, low cost, and high effectiveness, might act as a potential adjunct to various chemotherapeutic drugs.

Chemotherapy and radiotherapy Although tumor removal through surgical resection is essential for PC treatment, chemotherapy and radiotherapy are still required to control metastasis, minimize disease-related symptoms, and improve survival of patients. Few chemotherapeutic drugs are currently available for PC. Gemcitabine has been the most commonly used chemotherapy against metastatic PC since 1997 and is considered to be a safer drug than 5-fluorouracil (5-FU) owing to good survival rates in patients when it is used as a first-line therapy for the metastasized disease, as revealed by phase III clinical trials [18]. PC is the most commonly chemoresistant cancer owing to stromal microenvironment heterogeneity arising from the presence of CSCs, fibroblasts, immune cells, and pancreatic stellate cells responsible for developing resistance against various chemotherapy drugs including gemcitabine [19,20]. Developing effective strategies to combat resistance thus constitutes a major challenge in PC. Gemcitabine used with erlotinib or capecitabine has gained importance as a therapeutic strategy for PC. FOLFIRINOX, a combination drug of oxaliplatin, leucovorin, 5-FU, and irinotecan, is also recommended

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extensively against metastatic PC; however, its cytotoxicity in healthy cells, adverse reactions, and MDR limit its effectiveness [21]. In addition, a number of drugs such as everolimus and sunitinib have shown significant efficiency with good survival rates in PC but are limited by severe side effects such as neutropenia and anemia. Gemcitabine, branded as Gemzar, and NAB-paclitaxel, branded as Abraxane, a form of paclitaxel bound to the human albumin protein administered in a nanoparticle, have also shown good survival rates, as revealed by international randomized phase III trials [22]. Clinical trials investigating the efficiency of chemotherapeutic drugs against PC are summarized in Table 9.1. Moreover, a few molecularly targeted therapies have emerged and focus on suppressing oncogene expression, activating tumor suppressor genes, inducing apoptosis, and inhibiting growth factor receptors. These therapies include the use of monoclonal antibodies (Mabs) against target molecules. Nimotuzumab, cetuximab, and zalutumumab are a few Mabs used as antieepidermal growth factor receptor (EGFR) compounds. Drugs against PC include gefitinib and erlotinib (tyrosine kinase inhibitors) as well as bevacizumab and sorafenib, which are antievascular epithelial growth factor (VEGF) therapies. Radiation therapy, generally used to treat exocrine PC, is included in adjuvant therapy to lower the recurrence of the tumor and is given before and after resection along with chemotherapeutic drugs. Adjuvant therapy generally includes a combination of radiotherapy and chemotherapy. 5-FU, capecitabine, and gemcitabine are a few of the chemotherapy drugs administered in the adjuvant and neoadjuvant settings. Other therapeutic drugs include hydroxyurea and trimidox, which are ribonucleotide reductase inhibitors that enhance the radiosensitivity of PC cells with reduced cytotoxicity and clinical side effects in both preoperative and postoperative chemoradiotherapies [23]. Radiation therapy also incorporates x-beams of higher energy to destroy PC cells at their advanced stages and external shaft radiation to treat exocrine malignancies of the pancreas. Moreover, a proton accelerator is used to irradiate tumor cells using a proton beam with a fixed width within the Bragg peaks, following which cell proliferation and gene and protein expression are assessed. The process results in an increase of poly( adenosine phosphate-ribose) polymerase protein (PARP) levels, phosphorylation of histone H2AX, p21 upregulation, and a decrease in the homogenous repair enzyme RAD51 homolog1, a DNA repair protein. Lee et al. [24] determined that pancreatic cell line Capan 1 responds better to proton beam therapy compared with

Table 9.1 Ongoing clinical trials of chemotherapeutic drugs against pancreatic cancer (PC). Name of drug Combination Title Phase Description

mFLOX

Antroquinonol

BAY86-9766

NC-6004 (cisplatin formulation) Paclitaxel (Abraxane) Larotaxel

5-Fluorouracil (5FU) and oxaliplatin With NABpaclitaxel and gemcitabine Gemcitabine

With gemcitabine or gemcitabine alone Gemcitabine/ chemoradiation/ capecitabine 5-FU and capecitabine

Resveratrol

Abraxane

Gemcitabine

Source: www.clinicaltrials.gov.

Unresectable/ metastatic PC

Phase II

Metastatic PC

Phases I and II

Advanced/ metastatic PC

Phases I and II Completed Phase III

Advanced/ metastatic PC Advanced PC

Phase II/ completed

Advanced PC

Phase III/ completed

Low-grade gastrointestinal tumors PC

Phase III

Patients not eligible for 5-FU, leucovorin, irinotecan, and oxaliplatin will be treated with modified 5-FU and oxaliplatin Designed to evaluate the safety and efficacy of antroquinonol combined with NAB-paclitaxel and gemcitabine

High Cmax peak, high renal and neurotoxicity owing to cisplatin, thus combined with gemcitabine

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Panc-1 cells, which displayed an enhanced expression of survivin, indicating that survivin and RAD51 could constitute potent markers for proton beam therapy in PC. Radiation treatment is ineffective against neuroendocrine tumor (NET) of the pancreas but counters the metastasis of NET to bone or other tissue [25]. Multidrug resistance: MDR is a major hurdle detected in radiotherapy and chemotherapy and consists of the development of resistance against radiation and chemotherapy drugs by tumor tissue. Resistance that develop before treatment is known as intrinsic resistance. Alternatively, if resistance develops during treatment, it is termed acquired resistance [26,27]. Various factors involved in the emergence of resistance are listed next. Drug influx, efflux, and redistribution: MDR develops as a result of the overexpression of certain proteins including ATP-dependent multidrug transporter proteins or adenosine triphosphate (ATP)-binding cassette (ABC). These proteins can cause tumor cells to flush chemotherapeutic agents outside the cell against the concentration gradient, leading to the emergence of resistance owing to reduced drug concentrations resulting from its higher efflux [28]. There are 48 efflux transporter proteins in humans, including P-glycoprotein (P-gp/ABCB), ABCC, and ABCG [29,30]. Intrinsic drug resistance in the carcinomas of the pancreas, colon, kidney, and liver results from the high levels of expression of P-gp [31,32]. MDR proteins ABCC are known as organic anion transporters and lead to drug resistance in tumor cells by pumping out cytotoxic drugs and compounds of hydrophobic nature in the presence of glutathione [33], whereas ABCG leads to drug resistance by altering the concentration of drugs in the plasma [34]. In addition, tumor cells employ another mechanism called redistribution of the drug, in which the drug load in the intracellular cells is lowered, to escape treatment. This mechanism is regulated through an ABC drug transporter vault protein/lung resistance-associated protein and is most commonly detected in drugs interacting with DNA; it allows the drug to be redistributed from the nucleus to cytoplasm [35]. Chemoresistance developed in PC against 5-FU is caused by ABCC5 and ABCC11 [36e38]. In addition to ABC proteins, MDR transport proteins (MRP1, MRP3, MRP4, and MRP5) contribute to chemoresistance in PC because they are involved in the efflux of nucleoside analogues used for PC therapy. Nambaru et al. [39] suggested that MRP5 is highly expressed in PC cells and contributes to resistance against 5-FU. Gilzad et al. [40] pretreated PC with efflux proteins calcitriol, butylated hydroxytoluene, and butylated hydroxyanisole (BHA) and gemcitabine (influx) and determined that

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calcitriol increases gemcitabine uptake significantly and decreases the viability of cells, whereas BHA reduces the uptake, thereby decreasing the death rate. DNA damage repair mechanism: Tumor cells can also develop chemoresistance by activating DNA repair mechanisms, including the nonhomologous and homology recombination (HR) directed DNA repair pathways [41]. Certain factors, such as topoisomerase I and II, which are essential for repairing DNA double-stranded breaks, can be inhibited by chemotherapeutic drugs, but tumor cells alter them and thus develop resistance [42,43]. A group of epistatic radiation-sensitive (RAD) proteins including RAD51, RAD52, and RAD54 and replication protein A have major roles in HR repair of double-strand breaks of DNA [44]. DNA repair pathways and their kinases including DNA-dependent protein kinase, PI3K, and DNA ligase, combined with check point regulators such as Chk1 and Chk2 in tumor cells, can repair blueprint damage caused by toxic therapy [45]. The protein excision repair cross-complementing 1 protein is linked to the development of chemoresistance and is overexpressed in tumor cells [46]. Forkhead Box (FOX) gene, which regulates the cell cycle and overexpression of FOXMI, is detected in PC and contributes to invasion and epithelial mesenchymal transition (EMT). Paired related homeobox 1 was identified to have FOXM1 as its downstream target. It is also involved in response to DNA damage and its expression limits DNA damage induction. The inhibitor FD16, however, blocks FOXM1 and induces damage in DNA, regulating PC cell growth [47]. The germline mutation in tumor suppressor genes BRCA1 and BRCA2 impairs DNA damage repair and provokes genomic instability, leading to PC. These genes can be better targeted using DNA damaging platinum agents, as revealed in the analysis of 71 PC patients harboring BRCA gene mutations [48]. Furthermore PARP1, a chromatin-based nuclear binding enzyme, can induce various functions such as DNA repair, histone binding, and apoptosis, thus inhibiting PARP1, and thus could be beneficial for PC treatment. Clinically, PARP1 inhibitors have been used for breast and ovarian cancer therapy; clinical trials for PC and CRC therapy are ongoing. Food and Drug Administrationeapproved PARP1 inhibitors are olaparib, niraparib, and rucaparib. As these findings suggest, targeting DNA damage repair defects could be an emerging and effective strategy for PC therapy that warrants further testing [49]. Influence of apoptotic mechanism: Apoptotic mechanisms are another factor contributing to resistance in PC. Apoptotic pathways involved in this

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mechanism includes cytochrome/mitochondrial-mediated and death receptor pathways. The mitochondrial pathway is activated by procaspase and apoptotic protease activating factor 1, which induces caspase 9 [50]. p53 is an initiator of this pathway and activates the B-cell lymphoma family. Aberration in this pathway results in resistance against chemotherapy drugs because of the high frequency of p53 protein mutation [51], leading to the overexpression of B-cell lymphoma-extra large (Bcl)-2 and Bcl-xL and downregulation of p53 and Bax [52]. The Bcl-2 protein acts as a dual proand antiapoptotic protein. It is overexpressed in various tumors and is considered a key contributor to chemoresistance development [53]. The transmembrane extrinsic pathway activated by ligation of certain proteins such as tumor necrosis factorerelated apoptosis inducing ligand (TRAIL) activates caspase 8 and 10. Fas-associated protein with death domainelike interleukin (IL)-1econverting enzymes such as protease inhibitory protein (c-FLIP) and inhibitor of apoptosis (IAP) regulate the extrinsic pathway [54,55]. Furthermore, overexpression of certain survival proteins including survivin, c-FLIP, and X-linked IAP promotes chemoresistance [56e58]. miRNAs are small noncoding RNAs whose aberrant expression levels can lead to pathogenesis and dysregulated apoptotic mechanisms in various cancers including PC. For instance, miR-183 has been reported to have dual tumor-suppressive and oncogenic natures. Accordingly, it can inhibit PC growth and also increase survival, depending on the context of its expression [59,60]. Xiaoping et al. [61] reported that miR-183 inhibition increased apoptosis, decreased proliferation, and enhanced the sensitivity of PC cells against 5-FU and gemcitabine by regulating the phosphatase and tensin homolog/PI3K/Akt signaling pathway. A second miRNA, miRNA 132, was found to promote apoptosis, inhibit proliferation, and downregulate mitogen-activated protein kinase (MAPK)3 and nuclear transcription factor Y subunit a, as revealed by a bioinformatics analysis. Another oncogene overexpressed in PC is transcription factor FOXM1, which correlates with a poor prognosis and resistance against chemotherapy drugs such as gemcitabine in PC, affecting the signaling pathway of NF-kb. Its activity can be downregulated by interferon-gamma, thus enhancing sensitivity against gemcitabine, promoting apoptosis, and inhibiting PC proliferation, through phosphorylated STAT, which binds to FOXM1 and downregulates its transcription [62]. Metabolism and detoxification of chemotherapy drugs: The PC stroma is desmoplastic owing to pancreatic stellate cells that are activated by ROS, resulting in a myofibroblast-like phenotype that contributes to resistance

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against radiotherapy and chemotherapy drugs. Oxidative stress developed by PC cells results in the production of regulators such as Nrf2, which codes for detoxifying enzymes. Furthermore, the Nrf2 pathway can induce ROS detoxification and synthesis of purine nucleotides, which are then activated by mutations in KRAS [10], IL-6, and stromal derived factor-1a [63]. Also, the toxicity of chemotherapeutic drugs is regulated by drug metabolizing enzymes, which are overexpressed in tumor cells and reduce the concentration of drugs intracellularly. Conjugation enzymes (glutathione/glutathione S-transferase [GST], aldehyde dehydrogenase, and oxidative enzymes including cytochrome P-450 [CYP450]) have a significant role in protecting tumor cells against chemotherapeutic agents. They contribute to lipid metabolism, drug detoxification, and inflammatory metabolites by modifying the ends of fatty acids through the u-hydroxylase gene in CYP450. Thus, the presence of CYP450 isoforms in large concentrations in tumor cells could constitute a promising marker for differentiating between healthy and cancerous tissues. Moreover, CYP4A11 is overexpressed in PC cells, which suggests a role in promoting invasion, progression, and tumorigenesis [64]. In addition, upregulated GST activity contributes to the emergence of resistance against anticancer drugs including doxorubicin, cyclophosphamide, and mitomycin C [65]. The low activity of CYP450 also promotes chemoresistance against these drugs [66]. Furthermore, Diasio and Harris [67] reported that dihydropyrimidine dehydrogenase catabolizes 5-FU, leading to the development of chemoresistance in CRC. Alternatively, CSCs promote the initiation, metastasis, suppression of immunity, and resistance toward drugs [68]. CD133, ESA, CD44, and CD24 are reported to be pancreatic CSCs [69e73]. When exposed to chemoradiation, these CSCs promote stemness [74e76], activating various pathways including NFkb, PI3k/Akt, and Wnt. miRNAs have also been shown to regulate CSCs [69,73,77,78]. Signaling pathways: Survival pathways are characterized by a balance among pro- and antiapoptotic protein signaling, protein-like hormones, cytokines, and growth factors. However, mutation in these signaling pathways can lead to the development of tumor progression and resistance against chemotherapeutic drugs. Multiple pathways are implicated in the emergence of chemoresistance, including KRAS, Akt, NFkb, STAT-3, and EGFR, which form interlinked signaling networks. Mutation in KRAS induces the oversecretion of transforming growth factor-b and IL-10 and stimulates various downstream pathways (RAF/mitogenactivated protein kinase kinase [MEK]/extracellular signaleregulated

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kinase [ERK] and PI3K/Akt) [79]. Aberrant activation of Akt leads to resistance against chemotherapy and radiotherapy [80]. EGFR has a major role in various cellular processes. Hence, overexpression of EGFR and its associated downstream cascades, including MAPK and PI3K/Akt, can result in drug resistance [81e83]. Huang et al. [84] reported that Akt inactivation enhances doxorubicin activity. Akt also activates NFkb, which regulates over 500 genes. Hence, it activates numerous proapoptotic genes such as TRAIL and antiapoptotic proteins such as IAP and Bcl-xl [85]. Another key molecule, STAT3, is a transcription factor regulated by epidermal growth factors, cytokines including IL-6, and platelet-derived growth factors, contributing to chemoresistance [86e90]. Furthermore, the signaling pathway of Notch has a crucial role in PC progression. Although its involvement in pathogenesis is still unclear, the Notch pathway can interact with other signaling pathways including MEK/ERK, Wnt, Hedgehog (Hg) and many others to induce ɣ-secretase secretion involved in differentiation and metastasis in pancreatic stellate cells (PSCs) [91e93]. Furthermore, the Hg pathway modulates the stromal environment, growth of PSCs, and CSCs by binding to receptor protein, pitched homolog 1. This pathway remains active owing to increased availability of Hg ligand in the tumor microenvironment, leading to the internalization, degradation of smoothened (SMO) protein, and translocation of transcription factors glioma-associated oncogenes (GLI1 and GLI2), which are essential for the transcription of genes responsible for the development of the extracellular matrix [94]. Chemoresistance and the devastating outcomes of traditional therapies have led to increased interest in nontoxic natural phytochemicals as potential medical approaches to reduce cancer risk. Among these compounds, Res is a promising antineoplastic agent that has gained attention because of its multitargeting nature in various cancers. The following sections explore the potential of Res as a promising adjunct for chemosensitization in inherent and acquired resistant PC cells.

Resveratrol Resveratrol (Res), a natural phytoalexin polyphenol from the stilbene family, is extracted from the skin of hellebore, red grapes, peanuts, and berries. It is used in traditional Chinese (Polygonum cuspidatum) medicine

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[20,95]. As epidemiological studies have revealed, Res has a role in the French paradox and has attracted research interest owing its anticarcinogenic, antiinflammatory, antidiabetic, and antiaging properties. As demonstrated by Jang et al. [96], Res is a chemopreventive phytochemical and possesses anticancer properties in various tumors including lung, hepatocellular, prostate, and skin. It also has the ability to inhibit the initiation, promotion, and progression of tumor cells [96]. Qinhong et al. [20] proposed a categorized therapeutic strategy in which Res is first administered initially to patients before surgery to inhibit proliferation, induce apoptosis, and decrease the tumor volume; then it is given in the postoperative period to prevent tumor invasion and metastasis; and finally, it is administered combined with radiation and chemotherapy drugs to sensitize PC cells. Res has been found to resensitize tumor cell lines of the pancreas, breast, prostate, and so on by modulating certain survival proteins (survivin) and apoptotic proteins (Bax, caspases, and Bcl-2) to chemotherapy drugs (Taxol, doxorubicin, actinomycin D, and methotrexate) [97]. It is multitargeting and inhibits multiple molecules including transcription proteins, apoptotic proteins, DNA repair proteins, and various other biochemical pathways such as PI3K, Akt, NFkb, and Hg. Hg signaling is essential in the embryonic development of the pancreas and may have a mediating role in PC [98]. Res can decrease its expression by downregulating GLI1 and SMO, important molecules of the Hg pathway [99]. In addition, Res can lower the level of ROS in cancer cells and induce cellular aging and apoptosis (Fig. 9.1) [100]. Hyperglycemia, oxidative stress, and resistance toward insulin are principal causes of diabetes mellitus and are common factors responsible for promoting tumor growth. Res can inhibit PC progression by suppressing hyperglycemia and inhibiting migration to vascular smooth muscle induced by glucose through inhibition of ERK, p38, MAPK, and NFkb signaling pathways. In addition, it can induce invasion and migration of PC cells by suppressing H2O2 [6]. Res can inhibit PC growth, invasion, and EMT though matrix metalloproteinase (MMP)-2, E-cadherin, MMP-9, vimentin and N-cadherin [101e106]. Sanjit et al. [102] showed that Res can cause cell cycle arrest in PC at G1 by upregulating p21 and p27 expression, inhibiting cyclin D expression. This indicates that it can be used as a combinational therapy. Moreover, Res can induce apoptosis by inducing caspase 3/7 and suppressing Bcl-2 in PC [107]. Lei Yang et al. [106] reported that Res has a

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Figure 9.1 Schematic diagram showing possible mechanisms by which resveratrol (Res) alters pancreatic cancer cell proliferation and apoptosis. Res induces DNA damage by upregulating Nrf2, which inhibits reactive oxygen species (ROS), leading to DNA damage, which in turn leads to apoptosis. Res also inhibits transcription factors (TFs). Other mechanisms of action include the activation of caspases and Bax proteins. Bcl2, B-cell lymphoma 2; Cox2, cyclooxygenase-2; Nrf2, nuclear factor erythroid 2.

dual nature in PC cells. Thus, it can suppress and activate the tumor by upregulating Bax and VEGF-B, respectively. VEGF-B controls the phosphorylation of GSK-3b, a protein kinase implicated in tumor progression. They also indicated that Res may decrease the activity of glycogen synthase kinase 3b (GSK-3b) by inhibiting VEGF-B, which could represent a strategy to control the progression of PC when combined with metformin [106]. Res was also used in combination with TRAIL to resensitize PC cells to treatment by inhibiting NFkb and inducing apoptosis. An orthotopic mouse model was also used to test whether Res could enhance the antitumor action of gemcitabine [108,109]. In addition, as epidemiological studies indicate, risk factors causing PC include chronic stress, which activates hypoxia-inducible factor 1a (HIF-1a). Interestingly, Res was shown to mediate HIF-1a inhibition by suppressing ADRB, an HIF-1a downstream protein [110]. Under oxidative stress conditions, PSCs produce H2O2, inducing ROS to promote glycolysis, which is essential for the progression of tumor cells. Res downregulates the expression of glycolytic enzymes and inhibits miR-21, which enhances glycolysis, decreasing the invasive properties of PC cells [111].

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Resveratrol as an adjunct to chemotherapeutic drugs As revealed from in vivo and in vitro studies, Res can sensitize tumor cells to chemotherapy by regulating apoptosis and inhibiting proteins implicated in proliferation, the differentiation of tumor cells, and drug transportation implicated in chemoresistance. Research has shown that MDR can be classified as extracellular or intracellular. The intracellular mechanisms are atypical or classical. Atypical mechanisms occur sporadically but classical ones are the most commonly observed. The ABCB1 gene, which encodes a P-gp, acts as an ABC transporter with multiple domains. It is responsible for transporting drug particles and its overexpression can lead to drug resistance in PC cells [112,113]. Andreia et al. [114] used doxorubicin (DOX) combined with Res to reinstate drug activity. They found that Res improved the accumulation of DOX intracellularly. Sylwia et al. [7] investigated whether Res could resensitize tumor cells to daunorubicin and mitoxantrone and found that it resensitized tumor cells by blocking the cell cycle at different phases (G1eS/G2eM). The YES-associated protein (YAP) is another protein increased in various malignancies including liver, breast, lung, and PC. YAP is implicated in the Hippo pathway and its abnormal expression can cause chemoresistance in PC cells. Zhengdong et al. [115] reported that Res can resensitize PC cells to gemcitabine by suppressing the transcriptional activity of YAP through inducing adenosine monophosphate-activation protein kinase (AMPK). Res has also been found to target other signaling cascades. For instance, nutritive deprivation autophagy factor-1 (NAF-1), a protein expressed in the mitochondrial membrane and endoplasmic reticulum, contributes to apoptosis evasion and calcium metabolism. Its levels of expression are increased in younger mice compared with older ones [116]. Furthermore, NAF-1 deficiency can result in damage to organelles including mitochondria, leading to autophagy, whereas its overexpression can cause proliferation and tumor growth [117]. Because Res is an antioxidant phytochemical, it can inhibit the expression of NAF-1 by activating the Nrf2 pathway, resulting in ROS accumulation (Fig. 9.1) [118]. Nrf2 is a transcription factor upregulated in various cancers. Its activity remains controversial, but it can act as both a tumor promoter and suppressor, depending on the context. Cheng et al. [118] used Nrf2, activated by Res, to inhibit nuclear factor 1 and suppress the growth of PC cells (Fig. 9.1).

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Res was also found to resensitize PC cells to gemcitabine by targeting NAF-1. In addition, Res has been shown to exert radiosensitizing activity by potentiating ceramide levels induced through radiation, inhibiting the activity of COX-1, and suppressing NF-kb activity [119,120]. Shankar et al. [107] used a Kras G12D mouse model of human PC to investigate the activity of Res as a radiosensitizer against Nanog, a transcription factor. Furthermore, Res can enhance the cytotoxicity of various other chemotherapies such as paclitaxel, thalidomide, cisplatin, and velcade in different cancers. Hari et al. [109] reported that Res can sensitize PC cell lines to gemcitabine by inhibiting the expression of COX-2, cyclin D1, Bcl-2, Bcl-xL, VEGF, and MMP-9 and inactivating NF-kb expression. Bernhaus et al. [121] reported that an analogue of Res, N-hydroxy-N0 (3,4,5-trimethoxyphenyl)-3,4,5-trimethoxy-benzamidine, is an anticancer agent that has synergistic effects in combination with gemcitabine. Sterol regulatory element binding proteins (SREBPs) modulate genes responsible for cholesterol and lipid synthesis. Findings showed that SREBPs promote PC development and their inhibition by chemotherapy drugs can block tumor growth [122e124]. Gemcitabine can target these proteins, but it has also been shown to induce stemness in pancreatic CSCs. To overcome this shortcoming, Zhou et al. [125] used Res to improve gemcitabine activity, thus blocking the expression of SREBP1 in PC cells and suppressing stemness induced by gemcitabine in PCSCs [125]. Studies in other gastrointestinal malignancies such as colon cancer showed that Res can exert synergistic effects by resensitizing tumor cells to 5-FU through caspase activation and increased apoptosis [126]. The ribonucleotide reductase (RNR) enzyme is implicated in DNA replication and repair, producing deoxyribonucleoside triphosphates. Because PC cells develop resistance against gemcitabine, Chen et al. [127] identified a novel analogue of Res called trans-4-40 -dihydroxy stilbene (DHS), which inhibits RNR by targeting the regulatory subunit M2 of RNR, as revealed by molecular docking studies, inhibiting DNA replication and cell cycle arrest at the S phase. Hence, the analogue DHS can be used either as an adjunct with gemcitabine or alone to arrest the cell cycle. The phytochemicals used as an adjunct with chemotherapy drugs are summarized in Table 9.2.

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Table 9.2 Natural chemopreventive agents as potentiating adjuncts to chemotherapeutic drugs against pancreatic cancer. Chemopreventive Chemotherapeutic adjuncts drugs Trials References

Resveratrol

Gemcitabine

Curcumin

Gemcitabine

Genistein

Sulforaphane

Paclitaxel Celecoxib Docetaxel, cisplatin Erlotinib Tumor necrosis factorerelated apoptosis inducing ligand

In vitro and orthotopic In vitro and orthotopic In vitro In vitro In vitro In vitro In vitro and xenograft

Aggarwal et al. [120]

Bernhaus et al. [121], Bhutia et al. [132], Dong et al. [133] and Goldstein et al. [122] Li et al. [123] and Porstmann et al. [124] Cheng et al. [118]

Conclusions MDR constitutes a major obstacle in cancer therapy owing to its multifactorial nature and the emergence of mutations that prevent apoptosis. Conventional therapies based on the one drugeone target conundrum have failed to improve survival, which suggests that combinational therapy may be a more promising approach to overcoming MDR by blocking the pathways involved in mutations. In this regard, research indicates that combining Res and chemotherapeutic drugs may represent an attractive strategy for bypassing chemo- and radioresistance by targeting signaling pathways implicated in resistance and resensitizing tumor cells to therapeutic drugs. Elucidating the molecular framework and pharmacokinetic and bioavailability of these naturally available drugs is thus crucial. The antitumor activity of Res, although promising, remains limited by its low bioavailability [128,129]. Modifications in its molecular formula could enhance its bioavailability, rendering it more clinically effective. For instance, Jing et al. [130] reported a novel analogue derivative of Res named triacetyl resveratrol, which showed antitumor activity equal to that of Res with ameliorated pharmacokinetic characteristics including better half-life and volume distribution with enhanced interaction of phospholipid bilayers [131]. As these various findings suggest, an increased understanding

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of survival and MDR mechanisms will inform the design of novel natural therapeutic agents with improved antitumor activity. Extensive studies will be necessary to confirm the efficacy of these drugs in combinational regimens as potentiating adjuncts capable of resensitizing PC cells to chemotherapeutic agents.

Funding None.

Conflict of interest All authors declare no conflict of interest.

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