Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. The standard first-line treatment for PDAC is gemcitabine chemotherapy which, unfortunately, offers only limited chance of a lasting cure. This review further evaluates the hypothesis that the effectiveness of gemcitabine can be improved by combining it with evidence-based complementary measures. Previously, supported by clinical trial data, we suggested that a number of dietary factors and nutraceuticals can be integrated with gemcitabine therapy. Here, we evaluate a further 10 agents for which no clinical trials have (yet) been carried out but there are promising data from in vivo and/or in vitro studies including experiments involving combined treatments with gemcitabine. Two groups of complementary agents are considered: Dietary factors (resveratrol, epigallocatechin gallate, vitamin B9, capsaicin, quercetin and sulforaphane) and nutraceutical agents (artemisinin, garcinol, thymoquinone and emodin). In addition, we identified seven promising agents for which there is currently only basic (mostly in vitro) data. Finally, as a special case of combination therapy, we highlighted synergistic drug combinations involving gemcitabine with “repurposed” aspirin or metformin. We conclude overall that integrated management of PDAC currently is likely to produce the best outcome for patients and for this a wide range of complementary measures is available.
1. Introduction
Pancreatic cancer, the most common form of which is “pancreatic ductal adenocarcinoma” (PDAC), is one of the hardest to treat cancers both because of the difficulty of early diagnosis and the limited effectiveness of the available therapies (Citation1–3). With a five-year survival rate of only some 6%, the associated mortality rates are regional (deaths per 100,000 people) being ca. 7.2 (Europe), 6.5 (North America) and 1.2 (East Africa) (Citation4). PDAC is age-related; its incidence has been rising steeply for a number of years, and it is expected to become the most common cause of cancer-related deaths in the USA by 2030 (Citation5). PDAC arises in the pancreatic ducts which perform the gland’s main exocrine functions. The liver is often the first major organ to be metastasized due to the proximity of the hepatic portal vein (Citation6). In fact, liver failure is frequently the first sign and the main cause of death from PDAC. In the context of integrated management, therefore, treatments should ideally protect also the liver.
The most common first-line treatment for PDAC is gemcitabine chemotherapy (Citation7, Citation8). Gemcitabine is an “antimetabolite” pro-drug which becomes active once phosphorylated into diphosphate or triphosphate inside cells at very specific phases of the mitotic cycle. Thus, it works most effectively on fast-dividing cells, hence cancer cells. The basic mechanism of cell death is DNA damage (Citation9). Apart from its inherent limited effectiveness and the common undesirable side effects of the treatment, use of gemcitabine suffers from the eventual onset of resistance to the drug. In these respects, therefore, any adjustment to gemcitabine chemotherapy that will increase its sensitivity (and hence lower its dosage of use) and lengthen its period of effectiveness (e.g., overcoming resistance) would be welcome. Our hypothesis is that these are possible by combining the gemcitabine chemotherapy with evidence-based complementary agents. Indeed, use of complementary agents in cancer treatment generally is increasingly, being favored by patients as well as by oncologists (Citation10–14).
In the first instance, an association between dietary/nutritional lifestyle and PDAC is apparent epidemiologically from the fact that the PDAC incidence and mortality rates are much higher in relatively developed countries with diets rich in fatty, oily or sweet foods (Citation4). Whilst our understanding of this association has come a long way over the years, we know much less about how dietary and nutraceutical agents, as well as lifestyle factors, could associate with PDAC during treatment (Citation15). In our previous review, we advanced the hypothesis that the best outcome for PDAC currently would be obtained by integration of clinical medicine with evidence-based natural complementary agents and lifestyle factors (Citation16). Of the former, 9 (six dietary and three nutraceutical compounds) were chosen based upon evidence from clinical trials as the essential criterion, as well as meta-analyses and in vivo and in vitro experiments. In addition, however, there is a range of natural agents that did not meet all of those strict criteria but may do so in the future as more evidence is gathered. Here, we evaluate this second group of “emerging” agents incorporating both dietary factors and nutraceuticals. For all these, there is both in vivo and/or in vitro evidence including combination treatments. in vivo animal models include molecularly appropriate transgenic models wherever possible. As regards in vitro experiments, the data used come mainly from human cells.
Central to our approach, again, is the epigenetic nature of cancer, including PDAC, which means that genes and their products can be regulated significantly including by dietary and lifestyle factors (Citation16–20). Indeed, overall, ca. 40% of cancers are due to modifiable, hence reversible factors (www.cancer.org/latest-news/more-than-4-in-10-cancers-and-cancer-deaths-linked-to-modifiable-risk-factors.html). Not surprisingly, therefore, the link between nutrition and cancer has been questioned for over a century (Citation21). Since pancreas is a strongly hormonal (both endocrine and exocrine) organ, PDAC would be expected to be particularly sensitive to the body’s biochemistry and chemical balance (e.g., Refs. (Citation22–25)).
2. Dietary Factors
In our previous review we considered dietary factors in 3 different categories (Citation16). General/background conditioners included acidity, glycaemic index and cholesterol. As multifactorial foodstuffs, we covered red and processed meat, fish, fruit and vegetables, dairy, honey and coffee. Finally, as specific dietary agents the following satisfied our full criteria: Vitamins A, C, D, and E, curcumin and genistein. Here, we have accepted for further consideration six specific dietary factors for which significant in vivo and in vitro data were available. The emphasis again is on the possible potentiating effect of these agents on gemcitabine chemotherapy. Such dietary agents can also be taken as supplements.
2.1. Resveratrol
Resveratrol is a natural phytoalexin that is produced in plants as a defensive response against fungal infections and other environmental stressors. It is particularly abundant in the skin of red grapes, blueberries, raspberries, mulberries and nuts (). Resveratrol has been shown to inhibit proliferation and invasiveness of PDAC cells by reducing “nuclear factor κ-light-chain-enhancer of activated B cells” (NF-κB) expression, downregulating lipid metabolism and activating pro-apoptotic caspase-3 (Citation25–27). Furthermore, markers of epithelial-mesenchymal transition (EMT), an early event in invasiveness, were suppressed (Citation28). A synthetic, more stable derivative of resveratrol (triacetyl resveratrol) also selectively induced apoptosis in PDAC cells in vitro without affecting normal pancreatic ductal cells and this occurred via downregulation of hedgehog signaling (Citation29). Combined treatment of PDAC cells with gemcitabine and resveratrol (i) increased apoptosis highly significantly and (ii) reduced gemcitabine resistance in vitro and this involved adenosine monophosphate kinase (AMPK) (Citation30, Citation31). Also, in vitro, the inhibition of colony formation by gemcitabine was enhanced by resveratrol addition, again, involving an enhanced pro-apoptotic effect () (Citation27). Consistent with this, in an in vivo orthotopic mouse model of PDAC, the anti-tumorigenic effect of gemcitabine was potentiated by combination with resveratrol () (Citation32). These results were confirmed by Gupta et al. and Xu, Q. et al. (Citation33, Citation34). Importantly, also, resveratrol suppressed both the “basal” stemness of PDAC cells and that promoted by gemcitabine () (Citation27). In addition, pterostilbene, a natural analogue derived from resveratrol, enhanced gemcitabine sensitivity in part by inhibiting expression of the multi-drug resistance gene, MDR1 (Citation35).
Interestingly, addition of resveratrol to the combined application of gemcitabine and capsaicin restored the effectiveness of chemotherapy and increased radiosensitivity in in vivo (xenograft) models of human PDAC (Citation36, Citation37). These studies would raise the possibility of extending the integrated management to triple (or more) combinations without incurring antagonism, as we suggested earlier (Citation16). Finally, resveratrol reduced the undesirable side effects of chemotherapy on heart and liver by increasing the activity of antioxidant enzymes (Citation38).
In conclusion, resveratrol has excellent properties both by itself as an anti-PDAC agent and for possible integration with gemcitabine chemotherapy in the future.
2.2. Epigallocatechin Gallate
Epigallocatechin gallate (EGCG) is abundant in teas, especially green tea, and fruits, especially berries (). Epidemiological studies have shown beneficial effects of green tea on cancers of lung, breast, esophageal, stomach, liver and prostate (Citation39, Citation40). As regards PDAC, however, such studies have given somewhat inconsistent results. Most meta-analyses concluded (i) that green tea consumption was not associated with PDAC risk and (ii) that high consumption was associated with slightly lower risk (Citation41). This seemed more pronounced among Chinese populations (Citation42, Citation43). Abe et al. recently evaluated the available epidemiological evidence for green tea consumption and showed that whilst PDAC risk was not affected, several other cancers were associated significantly with reduced risk (Citation44). These included, importantly, liver cancer. Possible reasons for the discrepancy between the epidemiological data could include (i) the ranges of green tea consumption and (ii) compounding lifestyle factors especially smoking. Importantly, however, no adverse effect has been reported. Furthermore, green tea consumption could be beneficial indirectly by reducing the impact of diabetes, obesity and inflammation including pancreatitis (Citation40, Citation45–47).
There is a wealth of in vitro evidence showing that green tea and one of its most active ingredients, EGCG, inhibit development and progression of cancer, including PDAC (Citation48, Citation49). As regards “combination therapies,” an initial in vitro study suggested significant synergistic effects of gemcitabine with EGCG (over a range of concentrations). This involved increased expression of “signal transducer and activator of transcription 3” (STAT3) target genes and enhanced apoptosis () (Citation50). More recently, EGCG was able to enhance the gemcitabine-induced reduction in insulin-like growth factor receptor and Akt/protein kinase B signaling, and thus reduce cell migration and invasion in vitro () (Citation51). in vivo also (xenograft mouse model of PDAC), intraperitoneal EGCG downregulated glycolysis and potentiated the effect of gemcitabine, together reducing tumor weight by an additional ca. 30% () (Citation52).
In conclusion, the evidence for EGCG as an anti-PDAC agent is overall positive, albeit limited. The evidence is stronger for liver cancer. Hence, this agent would be worth considering for possible integration with gemcitabine chemotherapy in the future.
2.3. Vitamin B9
Vitamin B9 (folate) is one of eight B vitamins. It is abundant in foods such as citrus fruits, green leafy vegetables and legumes () (Citation53). Taken as folic acid, it is converted to folate by the body. Folate deficiency has been shown to induce chromosomal breaks and mutations in tumor suppressor genes, hence its supplementation proved beneficial against PDAC (Citation54). The level of reduced risk from increased folate intake varied between studies, but importantly, no adverse effect has been reported (Citation53, Citation55). Lin, H. et al. found in a meta-analysis that a high intake of folate, especially as part of diet, reduced the relative risk of PDAC by as much as 34% () (Citation53). This conclusion was supported by Yallew et al., also reporting a significant inverse association between folate intake and PDAC (Citation56). Studies have suggested that folate supplementation may be most beneficial when taken with certain folate-rich foods, e.g., spinach and asparagus (Citation56). Although vitamin B9 has not been tested in combination with gemcitabine systemically, it is one of the four components of the FOLFIRINOX regime, which is given to cases advanced (metastatic) PDAC. So, it can be considered acceptable for integrated management of PDAC.
In conclusion, we consider vitamin B9 to be an effective complement to gemcitabine chemotherapy of PDAC. We should note, however, that B vitamins are sometimes taken as a “complex” of the various forms, but this should best be avoided, since there is some evidence that B12 may promote cancer including PDAC (Citation57). The latter is consistent with dietary sources of B12 (animal products such as meat, dairy etc.) also being undesirable (Citation16).
2.4. Capsaicin
Capsaicin is the active ingredient of hot red peppers () (Citation58). It has anticancer properties through its ability to induce cell cycle arrest and cause apoptosis (Citation58). Capsaicin reduced the growth of PDAC xenografts in mice by promoting apoptosis mediated by caspase-3 and caspase-8 (Citation59). Additionally, capsaicin downregulated PI3 kinase signaling, leading to an increase in cell cycle arrest. Through the inhibition of the mitochondrial electron transport chain, capsaicin could generate reactive oxygen species (ROS) and increase DNA damage, without affecting healthy pancreatic cells (Citation60). There is no study on the possible effects of combining capsaicin with gemcitabine. However, in cases where gemcitabine monotherapy was ineffective, supplementation with capsaicin and resveratrol restored the full effectiveness of gemcitabine in vivo () (Citation37). This effect occurred through apoptosis. If, however, gemcitabine was at its full effectiveness, no increase following treatment with resveratrol and capsaicin was observed. Combinations of resveratrol and capsaicin were also able to sensitize some PDAC cell lines to radiotherapy, leading to further reduction in tumor volume in vivo () (Citation36). Capsaicin may also benefit patients through pain relief and reduction of inflammation (Citation61).
In conclusion, capsaicin has excellent properties for possible integration into management of PDAC, both directly and as regards side effects of the treatment.
2.5. Quercetin
Quercetin (also known as sophoretin or meletin) belongs to the flavonoid group of polyphenols and found naturally in apples, grapes, red raspberry and onions (). Although by itself it is not readily bioavailable, its various metabolites (present in systemic circulation after consumption) demonstrate significant biological (antioxidant and anti-inflammatory) activity. In vitro, quercetin suppressed a range of PDAC cell behaviors by regulating a variety of signaling pathways. Cell viability was suppressed dose-dependently () (Citation62, Citation64). Apoptotic cell death was increased significantly () (e. g., Ref. (Citation63)). The pro-apoptotic/anti-tumor effect of quercetin was confirmed in frozen tissue sections of human PDAC xenografts and shown to involve miR-let-7c as an intermediary (Citation65). Importantly, also, in human primary PDAC cells, quercetin upregulated miR-200b-3p expression and inhibited Notch signaling, resulting in inhibition of stemness and self-renewal (Citation66). Parallel to these effects, quercetin strongly downregulated the expression of a range of EMT markers () (Citation28, Citation64). Consistent with these effects, taken together, cellular invasiveness was significantly decreased, and this was dose dependent () (Citation64).
There is also some evidence from human PDAC cells in vitro that quercetin potentiates the effectiveness of gemcitabine in inhibiting cell viability and promoting apoptosis (). Also, on two human PDAC cell lines, Serri et al. used biodegradable nanoparticles and showed, again, that quercetin could enhance the impact of gemcitabine on cell viability by 15–20% (Citation67). Consistent with these results, Lan et al. showed that quercetin had a remarkable pro-apoptotic effect on a gemcitabine-resistant variant of Mia-Paca-2 cells () (Citation62). This was extended recently to several other gemcitabine-resistant PDAC as well as hepatocarcinoma cell lines by Liu ZJ et al. (Citation68). This effect was revealed to involve the “receptor for advanced glycation end products” (RAGE) (Citation62). In a further study, a natural isoform of quercetin, quercetin-3-O-glucoside, exhibited synergy with low concentrations of gemcitabine on human PDAC CFPAC-1 and SNU-213 cells in suppressing transverse migration induced by basic fibroblast growth factor (bFGF) (Citation69).
In vivo, also, quercetin caused a significant reduction of tumor volume in a xenograft model of PDAC, again involving let-7c () (Citation65). However, less work has been done to test the possible effectiveness of combining quercetin with gemcitabine in vivo. In the one available study, Angst et al. showed in an orthotopic model of PDAC that quercetin maintained its anti-proliferative and pro-apoptotic effects and reduced tumor weight (Citation70). In combination with gemcitabine, quercetin had a noticeably (ca. two-fold) greater effect on proliferative activity. In contrast, the additional effects of quercetin combined with gemcitabine on apoptosis and tumor weight were modest (ca. 10%). However, these effects did not reach significance, probably due to the limited number of animals used (n = 6) and the inherent variability of in vivo testing especially with combinations of agents (Citation70).
In conclusion, the evidence is consistent that quercetin suppresses PDAC and potentiates the effect of gemcitabine in vitro. In vivo, also, quercetin produces noticeable anti-PDAC effects, but more work is required to substantiate the evidence for the added benefit of combination with gemcitabine.
2.6. Sulforaphane
Cruciferous vegetables, named as such for their cross-shaped flowers, are rich in sulforaphane (other active ingredients include indole-3-carbinol and 3,3′-diindolylmethane). Sulforaphane-rich foods include broccoli, cabbage, cauliflower, brussels sprouts, collard greens and kale () (Citation71). Appari et al. showed that three servings of cruciferous vegetables per day was associated with a 50% decrease in PDAC risk (Citation72). A more extensive meta-analysis of four cohort and five case-control studies also found that a high intake of cruciferous vegetables decreased PDAC risk significantly by some 20% (Citation71). This was extended to a clinical trial (https://clinicaltrials.gov/ct2/show/NCT01879878). Thus, Lozanovski et al. reported that PDAC patients consuming sulforaphanes (freeze-dried broccoli) whilst undergoing palliative chemotherapy experienced improved survival albeit for limited time () (Citation73). A range of anticancer modes of action has been associated with sulforaphane (Citation76). In one study, indole-3-carbinol reduced the assembly of prostate cancer cells into organoids (Citation77). This finding could be significant to PDAC due to some similarities with prostate cancer, especially hormone (insulin) sensitivity. Both are also cancers of affluence and express similar stem cell markers (Citation78, Citation79). Sulforaphane suppressed the genetic damage of carcinogens, induced apoptosis and inhibited proliferation of PDAC cells, in culture as well as in vivo (Citation80). Specifically, combining sulforaphane with “tumor necrosis factor-related apoptosis inducing ligand” (TRAIL) was able to reduce resistance to the drug (Citation81). Furthermore, using a xenograft model of PDAC, synergy between sulforaphane and gemcitabine has been demonstrated in suppressing tumorigenesis and this involved suppression of Notch signaling and cancer stem cells (CSCs) () (Citation74). Finally, combining sulforaphane with radiotherapy suppressed PDAC cell viability by increasing cell cycle arrest () (Citation75). Interestingly, attempts are being made to develop stable synthetic variants of sulforaphane as anticancer drugs (https://evgen.com/).
In conclusion, the available evidence for sulforaphane is promising as regards its potential both as a preventative agent by itself as well as in combination with chemotherapy, including gemcitabine.
3. Nutraceutical Agents
Nutraceuticals are defined generally as natural substances that are not a part of normal diet but can be formulated and consumed as extracts or supplements. We have identified four nutraceutical compounds for which there are promising therapeutic effects (in vitro and/or in vivo) against PDAC and in some cases the associated organs, especially the liver (Citation82). These are listed in alongside their chemical formulae, main modes of action/cellular effects and natural sources.
3.1. Artemisinin
This compound is isolated from Artemisia annua, sweet wormwood, a herb commonly employed in traditional Chinese medicine against malaria (Citation83). Artemisinin and its derivatives (e.g., dihydroartemisinin) produced a variety of in vitro and in vivo effects against PDAC, including inhibition of growth and induction of apoptosis (Citation84–86). These effects have been associated with the upregulation of several miRNAs (Citation83). It has also been suggested that artemisinin generates ROS to induce oxidative stress and thereby cell death in PDAC cell lines (Citation87). Additionally, dihydroartemisinin increased T-cell proliferation and activity, which could promote an anticancer immune response (Citation88). Importantly, dihydroartemisnin increased the sensitivity of PDAC in vitro and in vivo to therapies including gemcitabine and TRAIL (Citation85, Citation89). In a xenograft model of PDAC, dihydroartemisinin significantly potentiated the effect of gemcitabine in supressing tumorigenesis by some 25% () (Citation85). Histochemical analyses of the tissues from the in vivo experiments showed that the enhancing effect of dihydroartemisinin involved suppression of proliferation and increased apoptosis () (Citation85). Additionally, dihydroartemisinin was able to sensitize liver cancer cells to gemcitabine in vivo, thereby further reducing tumor burden significantly (Citation90).
In conclusion, artemisinin and its derivatives can produce anti-PDAC effects and potentiate the effectiveness of gemcitabine. In addition, it may support liver function (). Altogether, therefore, it has great promise for integration into chemotherapy of PDAC.
3.2. Garcinol
This is a derivative isolated from Garcinia indica, a plant of the mangosteen family, commonly known as “kokum”. It is a potent inhibitor of histone acetyltransferases, a modulator of gene expression, both in vitro and in vivo. Garcinol could produce a variety of anti-PDAC effects, promoting apoptosis by increasing activities of caspase-9 and caspase-3 In Vitro (Citation91). By modulating the expression of miRNAs involved in chemoresistance, garcinol also allowed gemcitabine to become significantly more effective in suppressing proliferation and promoting apoptosis In Vitro (Citation92). Importantly, garcinol could also suppress the self-renewal and tumor-forming ability of CSCs (Citation93). Alone or in combination with gemcitabine, garcinol suppressed tumor growth in a transgenic (KPC) mouse model of PDAC () (Citation94). Furthermore, quantifying the stage of PDAC as pancreatic intraepithelial neoplasia (PanIN), combined treatment resulted in disease remaining in earlier stages. Thus, compared with gemcitabine treatment alone, PanIN lesions of all grades were consistently fewer in the combination treatment () (Citation94).
In conclusion, the available evidence suggests consistently that garcinol has significant effects against PDAC in vitro and in vivo and would seem ready to be tested in gemcitabine combination treatments.
3.3. Thymoquinone
This is an active ingredient isolated from the black seed, Nigella sativa (). It has been investigated for its anti-oxidant and anti-inflammatory activities against PDAC, both in vitro and in vivo, and was found to be effective without significant side effects (Citation95). Thymoquinone also has anticancer including anti-metastatic properties (Citation96). Mahmoud & Abdelrazek reviewed these properties as well as the hepatoprotective effects of thymoquinone (Citation97). Specifically, in PDAC, thymoquinone downregulated the expression of the anti-adhesive protein MUC4, thereby leading to decreased cell motility (Citation98). Several studies have suggested a synergistic effect of thymoquinone in combination with gemcitabine. When these agents were combined in vitro, cell viability fell by more than 50% compared with monotherapy () (Citation99). In a xenograft model of PDAC, combination of thymoquinone with gemcitabine produced a significantly greater effect (by some 80%) on tumor weight compared with gemcitabine alone () (Citation99). This effect involved potentiation of caspase (3 and 9) activation, leading to apoptosis (Citation100). This pro-apoptotic effect appeared to be specific to PDAC cells (Citation101). Thymoquinone-induced histone acetylation was proposed to be the basis of its synergy with gemcitabine (Citation102).
In conclusion, from the available in vivo combination evidence, supported by in vitro data, we conclude that thymoquinone has excellent potential to be incorporated into an integrated management regimen for PDAC.
3.4. Emodin
This is a purgative resin from rhubarb (Polygonum cuspidatum), buckthorn and Japanese knotweed (Fallopia japonica) (). By increasing activation of tumor suppressor genes via DNA demethylation, emodin suppressed PDAC cell proliferation (Citation103–105). In combined treatments in vitro, emodin “sensitized” a drug-resistant cell line to gemcitabine () (Citation105). In an orthotopic xenograft model of PDAC, emodin promoted the effect of gemcitabine in suppressing tumorigenesis () (Citation106). The effects of emodin involved increased apoptosis and inhibited angiogenesis with possible transcriptional control via NF-κB (Citation106–109). Finally, in a mouse model of PDAC, emodin dose-dependently decreased metastasis to liver by up to ca. 50% whilst “normalising” miR1271 expression and inhibiting EMT (Citation107). In vitro and in vivo, liver cancer itself benefited from emodin treatment which also enhanced the effectiveness of a biological (sorafenib) therapy (Citation110). Finally, also in an in vivo mouse model, cachexia could be reversed by long-term treatment with emodin and this occurred through decreased hypoxia inducible factor (HIF) - 1α signaling (Citation111).
In conclusion, emodin can produce beneficial effects against PDAC, as well as liver cancer, by itself and can potentiate the effectiveness of gemcitabine in vitro and in vivo. Thus, it could be considered for clinical application.
4. Further Emerging Potential Complementary Agents
We should note that there are a number of other “agents” (dietary and nutraceutical) with anti-PDAC properties but for which evidence is mainly from In Vitro experiments and no In Vivo combination data are available. Such emerging agents are noted here with the expectation that the evidence in their favor could become stronger in time. Some examples of these emerging agents include the following.
4.1. Lycopene
This is the red pigment that gives red and pink fruit, such as tomatoes, watermelons, pink grapefruit and guava their characteristic color. A meta-analysis of 18 eligible studies concluded that lycopene intake and PDAC risk were inversely correlated (Citation112). This conclusion was supported later by the mechanistic demonstration that lycopene induces apoptosis in PDAC cells (Citation113). Thus, the overall evidence for the anti-PDAC role of lycopene is significant. However, it has never been tested in combination therapies. Lycopene can also protect against acute pancreatitis and diabetes (e.g., Refs. Citation114, Citation115). Accordingly, lycopene may currently be used in a preventative setting. Although it is not known if it would potentiate gemcitabine chemotherapy of PDAC, it could reduce or even prevent the side effects of chemotherapy due to its antioxidant and anti-inflammatory properties (Citation116, Citation117).
4.2. Zinc
This is an essential mineral found naturally in high concentrations in oysters, crab, beans and pumpkin seeds. It is frequently mentioned as an anticancer agent but the evidence for its possible anti-PDAC effect is quite contradictory (Citation118–120). This is probably due to the multi-faceted role of this metal as a structural component of many proteins and a co-factor in enzymatic reactions. Overall, a meta-analysis concluded that high consumption of zinc was associated with a decreased risk of PDAC (Citation121). Consistent with this, more recent evidence has concluded that zinc dyshomeostasis (caused by the dysfunction of zinc transporters) can contribute to the initiation and/or progression of various cancers, including PDAC (Citation122). Accordingly, the zinc ionophore, clioquinol, was suggested to be efficacious against PDAC (Citation123). Furthermore, “Bhasma” (incinerated processed zinc widely used in Ayurveda for various ailments) could also be effective against PDAC (Citation124). Finally, zinc could protect against cachexia in PDAC (Citation125). While there is no evidence for possible synergy between chemotherapy and zinc, it has been deemed acceptable for treatment of liver disease (Citation126, Citation127).
4.3. Selenium
Selenium is a trace element that plants accumulate from soil and convert to organic forms. Thus, it is naturally present in many foods, especially Brazil nuts, seafood, pasta and eggs. Han X et al. originally reported anti-PDAC effects of selenium (Citation128, Citation129). A meta-analysis and a later nested case-control study found no adverse effect on PDAC but a negative association was apparent for patients with body mass index (BMI) higher than 25 (Citation130, Citation131). Beneficial effects and no adverse effects have also been reported against diabetes (Citation132–134). However, high-level consumption could promote insulin resistance and should be avoided (Citation135).
4.4. Magnesium
Magnesium-rich foods include dark-green leafy vegetables, seeds, wholegrains, fish and nuts. A recent study revealed significantly lower levels of magnesium in urine of PDAC patients compared to healthy controls (Citation136). Consistent with this, a prospective cohort study showed that magnesium supplementation may help prevent PDAC (Citation137). Mechanistic evidence suggested (i) that Mg2+-permeant ion channels associate with PDAC (Citation138) and (ii) that the Mg2+ transporter protein SLC41A1 could be a viable anti-PDAC target (Citation139). Indirectly, also, magnesium may reduce the risk of PDAC through its well-established negative relationship with diabetes (Citation140, Citation141).
4.5. Plumbagin
This is a derivative of naphthalene obtained from the roots of the “chitrak” that has been used in Ayuverdic medicine for more than 2,500 years. A bioinformatics study revealed several “mainstream” cancer signaling mechanisms whereby plumbagin could affect survival, apoptosis and metabolism in PDAC cells (Citation142). Indeed, experimentally, plumbagin has been shown to inhibit the growth of PDAC cells (including CSCs) and induce autophagy in vitro and in vivo and may target the tumor suppressor p53 (Citation142–145). Most recently, Pandey et al. showed that plumbagin induced apoptosis in PDAC cells both in monolayers and three-dimensional tumor spheroids (Citation146). This effect involved production of ROS and cleavage of caspases 3 and 9. Work is ongoing to develop nanoparticles of plumbagin as an anti-angiogenic drug (Citation147).
4.6. Milk Thistle
This has been used as a traditional herbal remedy for almost 2000 years. Its active ingredient, silymarin (major constituent, silibinin/silybin) has been shown to inhibit proliferative activity and angiogenesis in models of PDAC (Citation148). Silibinin also promoted viability and promoted apoptosis and autophagy in human PDAC cells (Citation149). These effects were mediated by increased “stress-activated protein kinase” (JNK/SAPK) signaling. Used by itself, silibinin could suppress tumor growth and cachexia in in vivo mouse models of PDAC (Citation150). Silibinin is also well known for its “hepatoprotective” property and for promoting liver regeneration (Citation151). Indeed, a randomized phase two clinical trial on childhood acute lymphoblastic leukemia (ALL) undergoing chemotherapy employed in combination silymarin (milk thistle extract) with the aim of reducing liver toxicity and a positive effect was reported (https://clinicaltrials.gov/ct2/show/NCT00055718) (Citation151).
4.7. Berberine
This is an isoquinoline alkaloid extracted from a variety of natural herbs (Citation152). Its molecular targets include upregulation of tumor suppressor genes, activation of AMPK and downregulation of matrix metalloproteinase production, leading to decreased cellular proliferation and invasion (Citation153). In vitro, berberine induced apoptosis and suppressed the CSC population in PDAC cell lines even more effectively than gemcitabine (Citation154, Citation155). Another study showed that berberine inhibited PDAC cell viability by dysregulating cellular energetics by targeting citrate metabolism (Citation156). In vivo, also, berberine could reduce tumor growth in mouse models of PDAC (Citation157). In addition, berberine demonstrated insulin-regulating properties and could suppress PDAC also indirectly (Citation158). Consistent with this, it could potentiate the therapeutic effect of metformin (see section 5.2) (Citation159).
4.8. Ginseng
Panax ginseng (“ginseng”) is a perennial plant that grows in East Asia. It is a traditional medicinal herb with a unique family of active saponin ingredients called “ginsenosides”. It is available in various forms (e.g., fresh, white, steamed, acid-processed and fermented) leading to a range ginsenoside compositions with diverse pharmacological properties (Citation160). Yun & Choi found in an early case-control study concluded ginseng consumption would reduce the risk of PDAC and liver cancer (Citation161, Citation162). Experimentally, extracts of ginseng (leaves, flowers and roots) and some nanoparticle preparations have been tested against various human PDAC cell lines and shown to inhibit cell viability, proliferation and angiogenesis whilst promoting apoptosis (e.g., Refs. Citation163–165). Some anti-PDAC effects have also been reported in vivo (Citation166, Citation167). Furthermore, ginseng could delay the development of type 1 diabetes and pancreatitis, both PDAC risk factors, in rats (Citation168, Citation169). Finally, ginseng has also been reported to enhance the effectiveness of in vitro gemcitabine (and some other chemotherapeutic agents) on PDAC cells as well as liver, lung and prostate cancers (Citation170–172).
5. Drug Combinations
Drug combinations refer to more than one drug being taken together. Although this topic is outside the immediate scope of the current review, as another “combination,” we would like to highlight it here for awareness and possible benefit to patients (Citation173). In fact, use of drug combinations is common in cancer therapy and is already applied to PDAC in the form of FOLFIRINOX. A novel approach is including in the combination a drug that has been developed and prescribed for conditions other than cancer (a practice known as “repurposing”). We highlight here two examples of such drug combinations.
5.1. Aspirin
This is a natural agent used commonly against pain and inflammation. Its general health benefits including anticancer properties have been highlighted over many years (Citation174, Citation175). However, caution has also been expressed as regards its possible detrimental side effects on uncontrolled high blood pressure, bleeding disorders, asthma and stomach ulcers (Citation176, Citation177). As regards PDAC, evidence suggests that high and medium usage (one or more 75 mg tablet a day) may reduce the risk by as much as 50%, the risk of those who stop taking it subsequently increasing (Citation178, Citation179). This is through its inhibition of the COX-2 enzyme which indeed is upregulated in PDAC and may promote the disease by enhancing inflammation, a risk factor for PDAC (Citation180). A negative association between aspirin use and PDAC risk was demonstrated from a meta-analysis () (Citation181, Citation183). The association was stronger with increased frequency and duration of aspirin consumption (Citation178, Citation181, Citation184). The apparent time-dependent correlation could be due to the fact that development of PDAC begins long before its diagnosis so, to derive benefit, consumption of aspirin should start well before occurrence (Citation185).
In terms of “combination therapy,” aspirin proved an effective adjuvant to gemcitabine in the treatment of PDAC in an in vivo transgenic mouse model (Citation186). This study also showed that the combined treatment prolonged survival by ca. 30% over gemcitabine treatment alone. In an extensive, combined in vitro and in vivo study, including cells taken from PDAC patients, aspirin (at clinical doses) enhanced the effectiveness of gemcitabine in suppressing tumorigenesis () (Citation182). The effect involved induction of apoptosis, reduction of cell viability and expression of proteins involved in inflammation and stem cell signaling (Citation182). This study also showed that the aspirin + gemcitabine combination significantly prolonged the survival of mice, by some 40%, compared with gemcitabine alone (). Importantly, also, aspirin sensitized cells that were resistant to gemcitabine (Citation182, Citation187). In a more recent phase 1b clinical trial, aspirin has been included as a part of an immunotherapy/vaccination regime against PDAC (Ref: CHUV-DO-0017_PC-PEPDC_2017) (Citation188).
In conclusion, aspirin can be taken safely in a preventative setting and can also be used in combination with gemcitabine chemotherapy to improve treatment efficacy.
5.2. Metformin
Metformin is the most common oral drug prescribed for type II diabetes (Citation189). Epidemiological evidence suggests that diabetics treated with metformin are less likely to develop PDAC (Citation190). Indeed, meta-analyses revealed that metformin treatment increased survival in diabetic PDAC patients as well as presumed non-diabetics (Citation190, Citation191).
By inhibiting oxidative phosphorylation, metformin reduces levels of the energy rich compound adenosine triphosphate (ATP) in cells, which in turn downregulates signaling mechanisms involved in cellular survival and proliferation (Citation192). Consistent with this, a study on a transgenic mouse model found that metformin reduced PDAC incidence (quantified by PanIN pathology) by up to 50% (Citation193). Importantly, in in vivo mouse models of PDAC, metformin reduced CSC proliferation as well as infiltration and activation of tumor-associated macrophages which contribute to desmoplasia (Citation194). Thus, metformin could induce stromal depletion and enhance penetration of a nanoparticulate form of gemcitabine (Citation195).
There is also increasing evidence that metformin can enhance the effectiveness of gemcitabine (Citation196, Citation197). Li, X. et al. performed a meta-analysis of rather disparate data and concluded that patients taking metformin (with or without chemotherapy) had improved overall survival compared with a control group not taking metformin () (Citation198). Subgroup analysis showed that the effect of metformin correlated with tumor stage and was associated with improved survival in patients who had surgery or locally advanced cancer, but not in patients with metastatic disease (Citation198).
The apparent improvement of effectiveness of chemotherapy by metformin is also supported by in vitro experiments involving several human PDAC cell lines (Citation202, Citation203). In another study, even resistance to gemcitabine was reversed by metformin, albeit in vitro (Citation204). Only one in vitro study reported inhibition of the pro-apoptotic effect of gemcitabine (Citation205). However, this study involved (i) murine cell lines and (ii) the concentration of metformin used (20 mM) was rather high (cf. Ref. Citation192). Also, in an in vivo mouse xenograft model of PDAC, metformin demonstrated antitumor activity against a drug-resistant tumor (Citation199). Combination of gemcitabine with metformin generated a noticeably further reduction in tumor weight, compared with the effect of gemcitabine alone () (Citation199). Furthermore, in xenograft and genetically engineered mouse models of PDAC, metformin enhanced significantly the effect of gemcitabine in improving survival () (Citation200). This enhancement effect was suggested to involve inhibition of CSCs and suppression of angiogenesis (Citation200, Citation206).
Synergistic effects of combining metformin with radiation (plus gemcitabine in some cases) were observed in PDAC cells in vitro () (Citation201). This “radiosensitization” effect was thought to involve AMPK (Citation201, Citation202).
Several clinical trials are evaluating the anti-PDAC potential of metformin by itself and in combined administration with chemotherapy (gemcitabine and nab-paclitaxel) and radiotherapy. The trials that have been concluded so far were those on late-stage or gemcitabine-resistant disease and, unfortunately, did not find significant improvement by adding metformin (Citation207, Citation208). Other trials are still to report.
In conclusion, there is promising preclinical evidence that metformin can be added safely as an adjuvant to chemotherapy of PDAC. Currently, this would appear more promising for early-stage disease.
6. Future Perspectives and Conclusion
In our previous study, supported by clinical trial data, we identified six dietary and three nutraceutical agents for integration with gemcitabine chemotherapy of PDAC (Citation16). Here, based upon more limited available evidence, we evaluated another 10 agents (six dietary and four nutraceutical) which, in due course, may be added to the kind of integrative scheme we presented earlier. In fact, remembering the direness of PDAC, these 10 agents could even be introduced into integrated management now since, although the evidence in their favor is limited, there is no associated adverse effect. In addition to the incorporation of such agents, one should remember that integrative lifestyle factors should also be considered for completeness. These would include limited alcohol intake, no smoking, and regular exercise and avoiding obesity (Citation16). In overall conclusion, cancer-causing processes can be suppressed, and current treatment methods can be potentiated significantly by integrating with complementary factors to the extent that it may ultimately be possible to live with cancer chronically () (Citation209). In fact, any improvement to life expectancy would be hugely beneficial to PDAC patients as research continues intensely in this field and new clinical therapies as well as novel integration regimes can be expected.
In further evaluating the kinds of dietary and nutraceutical agents covered here, a number of issues should be born in mind. These were covered in some detail by Jentzsch et al. (Citation16). Some key issues are the quality of the agents and the possible personalized nature of their effects. Future research should aim at ascertaining such issues as well as determining the molecular mechanisms/modes of action of the emerging agents and, most importantly, extending the evaluations to clinical trials.
In overall conclusion, both existing and emerging evidence strongly suggests that introduction of complementary agents and lifestyle factors into mainstream treatment of PDAC can produce significant beneficial effects, as regards both disease status and its side effects (Citation16, Citation210).
Abbreviations | ||
AMPK | = | Adenosine Monophosphate Kinase |
ASP | = | Aspirin |
CAPS | = | Capsaicin |
CSC | = | Cancer Stem Cell |
DHA | = | Dihydroartemisinin |
EGCG | = | Epigallocatechin Gallate |
EMO | = | Emodin |
EMT | = | Epithelial-Mesenchymal Transition |
FOLFIRINOX | = | Folinic acid + Fluorouracil + Irinotecan + Oxaliplatin |
GAR | = | Garcinol |
GEM | = | Gemcitabine |
MET | = | Metformin |
NF-κB | = | Nuclear Factor κ-light-chain-enhancer of activated B cells |
PDAC | = | Pancreatic Ductal Adenocarcinoma |
QUER | = | Quercetin |
RAD | = | Radiation |
RES | = | Resveratrol |
ROS | = | Reactive Oxygen Species |
SFN | = | Sulforaphane |
TRAIL | = | Tumor Necrosis Factor-Related Apoptosis Inducing Ligand |
TMQ | = | Thymoquinone |
Acknowledgments
This study was funded by The Sunflower Jam charity and is dedicated to the memory of Jon Lord. We thank Ms Vicky Lord and Ms Jacky Paice and, also, the College of Medicine, Dr Michael Dixon in particular, for encouragement. Our research – neuroscience solutions to cancer – overall is supported by the Pro Cancer Research Fund (PCRF).
Conflict of Interest
The authors declare no conflict of interest.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
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