Frontiers in Anti-Cancer Drug Discovery: Volume 5 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Anti-Cancer Drug Discovery
- Sprache: Englisch
Frontiers in Anti-Cancer Drug Discovery” is an Ebook series devoted to publishing the latest and the most important advances in Anti-Cancer drug design and discovery. Eminent scientists write contributions on all areas of rational drug design and drug discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. The Ebook series should prove to be of interest to all pharmaceutical scientists involved in research in Anti-Cancer drug design and discovery. Each volume is devoted to the major advances in Anti-Cancer drug design and discovery. The Ebook series is essential reading to all scientists involved in drug design and discovery who wish to keep abreast of rapid and important developments in the field.
The fifth volume of the series features chapters on the following topics:
-Nutraceuticals and natural food products for cancer treatment
-Pharmacogenomics in Anti-cancer treatment
-Cancer stem cells
-Potassium channel targeting for brain tumor treatment
-Sorafenib in the management of hepatocellular carcinoma
…and more.
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Seitenzahl: 524
Veröffentlichungsjahr: 2015
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Frontiers in Anti-Cancer Drug Discovery
Volume 5
Atta-ur-Rahman, FRS
M. Iqbal Choudhary
BENTHAM SCIENCE PUBLISHERS LTD.
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PREFACE
Prof. Atta-ur Rahman, FRSProf. M. Iqbal ChoudharyCancer remains a leading cause of death, despite decades of fundamental and applied research in this field. However, early diagnosis, better understanding of disease processes, preventive strategies, and development of new classes of anti-cancer drugs have contributed to improving the survival rate and quality of lives of cancer patients.
Volume 5 of “Frontiers in Anti-Cancer Drug Discovery” contains well written comprehensive reviews of various aspects of cancer biology, prevention and drug designing. These articles, contributed by leading experts, reflect the diversity and complexity of the research field, and where it stands today. This “must read” eBook is a comprehensive treatise of the state-of-the-art in cancer research.
The first two reviews in this volume relate to diet and its relationship to the on-set of cancer. Diet can be a part of the problem, or part of the solution. It can cause certain cancers, and also prevent cancers, depending on what you eat. Cancer prevention by using dietary agents is now one of the most active areas of research.
Gabriela Gutiérrez-Salmeán et al. review the various dietary components which are associated with increased risk of certain cancers. The authors have provided an interesting commentary on various classes of dietary agents, such as antioxidants, omega-3 fatty acids, and polyphenols which are perceived as cancer chemopreventive agents. The pitfalls of their use as adjuvants and the non-conclusive clinical data, is also vigorously debated.
Atanasova and Gatseva have contributed a comprehensive review of the results of various epidemiological studies on the reduced risk of cancers with the consumption of certain functional foods, rich in bioactive substances. The role of various types of carotenoids in cancer prevention is extensively reviewed in this article. Evidences are presented that antioxidant micronutrients of natural origin are far superior in providing cancer prevention than their synthetic analogs.
Bassam Abdul Rasool Hassan has reviewed the pivotal role of pharmacogenomics in cancer treatment. It is now well established that genetics plays a key role in the on-set and progression of cancer, as well as the therapeutic outcome. Intra-individual genetic variations directly affect the drug response. Therefore pharmacogenomics is increasingly used in cancer treatment. This interesting review narrates the role of pharmacogenomics in drug selection, dosage, duration of treatment, and safety and toxicity.
In silico methods continue to play an important role in drug discovery and optimization. Dutt and Madan review the systematic utilization of in silico approaches in accelerating drug discovery and designing drugs for cancer treatment. They have discussed the effectiveness of various in silico models, and machine learning techniques, employed for the development of novel anti-cancer agents.
Ali Zekri et al. uncover a novel aspect of cancer biology by reviewing the most recent literature on cancer stem cells (CSCs) as target for anti-cancer drugs. These cells are responsible for the heterogeneity of tumor mass, and are often resistant to standard cancer chemotherapies. The chapter highlights the importance of further studies in this exciting field.
The next three chapters focus on two key targets for anti-cancer drug discovery. Drug resistance in cancer cells is a growing threat to the effectiveness of current therapeutic regimen. Efflux pump p-glycoproteins (P-gp) play an important role in hindering cancer chemotherapy. Extensive research is being conducted targeting the p-glycoprotein efflux pump. The chapter by Mayur C. Yergeri describes the various classes of natural and synthetic compounds, which can selectively inhibit P-gp and other transporters.
Monde Ntwasa has contributed a review on small molecular activators of p53 regulatory machinery, which can serve as anti-cancer agents. p53 protein is down regulated or inactivated in many cancers, and factors which contribute to the inactivation of p53 protein can be targeted to upregulate its expression as a therapeutic strategy.
Ningaraj and Khaitan describe the role of ion channels [(Ca-dependent K+ channels (BKca) and ATJP-sensitive K+ (KATP) channels] in brain cancers which unfortunately have poor prognosis, and are often difficult to treat. They have presented the out-comes of their own work on BKca and KATP channels inhibitors which can enhance the delivery of antineoplastic drugs and imaging agents in cancer cells.
Agorastou and Tsoulfas have discussed the therapeutic potential of sorafenib, a multi-kinase inhibitor against Raf kinase, as a drug against hepatocellular carcinoma (HCC). Sorafenib can be used in different stages of cancer progression and apparently works as an anti-angiogenetic agent. The use of sorafenib, alone or in combination, and therapeutic outcomes against HCC are extensively reviewed.
This volume of the eBook series represents the results of a considerable amount of work by many eminent scholars. We wish to thank them all for their excellent contributions, and their commitment to complete the writing assignments in an efficient manner. We would also like to thank the excellent team of Bentham Science Publishers, especially Ms. Fariya Zulfiqar led by Mr. Mahmood Alam, Director Bentham Science Publishers, who deserve all appreciation.
Nutrition, Nutraceutics and Cancer
Gabriela Gutiérrez-Salmeán*,Alejandro Ríos-Hoyo,Huguette Ríos-Ontiveros,Ma José CortésAbstract
Cancer is a leading cause of death worldwide. Although genetics certainly plays an important role, environmental factors -i.e., overall lifestyle, including diet, physical activity, and nutritional status, among others- are known to be triggering factors for the development of many types of cancer. Different dietary components have been associated with the risk of developing cancer; these include alcohol, red (processed) meat, and low-fiber diets. On the contrary, physical activity and the practice of frequent exercise, together with an energetically-restrictive dietary regimen appear to reduce the risk of neoplastic diseases. Moreover, specific substances within food have been considered to exert biologically active properties and thus have been considered as attractive candidates to be used not as a sole approach but -maybe- as coadjuvant agents during cancer therapy. Such nutraceuticals include: antioxidants, sulphoraphane, omega-3 fatty acids, lycopene, and polyphenols, among other. Even though preclinical and small clinical trials have shown promising evidence, it is still inconclusive, hence no actual dosage recommendations can yet be emitted. These open an interesting and urgent research field within Nutrition and Oncology.
Introduction
Cancer is a leading cause of death worldwide. Although genetics and chronic exposure to certain specific agents (e.g., tobacco smoke, ionizing radiation, asbestos, arsenic, etc.) are considered as the primary risk factors within carcinogenesis, the overall lifestyle -including diet, physical activity, and nutritional status, among others- has been evidenced to play simultaneous and interrelated triggering roles for the development of many types of cancer.Nutrition, for its side, refers not only to the eating process, but instead to the series of physiologic events through which food is digested, absorbed, metabolized, and used by the body in order to maintain optimal health. Diet therapy, therefore, is not only important in order to prevent the development of disease -including cancer- but it is also of crucial importance during antineoplastic treatment of any patient as a well-nourished patient has a better overall prognosis in terms of oncologic response and survival, together with a decreased chance of presenting complications, toxicities, and cancer recurrence.
Moreover, the emerging field of pharmaconutrition and the use of functional foods and nutraceuticals (i.e., the use of specific foods or isolated nutrients aimed to give additional effects more than those “given as energy or nutrimental value” and often related to modulating health promotion and/or disease progression) have raised increasing interest in exploring the potential applicability of such agents, not as monotherapy, but as coadjuvant mediators of the primary treatment.
Due to the aforementioned, along this chapter, we present scientific evidence showing the relationship among diet, physical activity, nutrition status, and cancer; followed by a brief revision of specific dietary components under research due to their potential in the modulation of the carcinogenic process.
Lifestyle as the primary factor for preventing cancer: from diet and physical activity to nutritional status
Research has shown that up to 30% of cancers can be prevented through diet and regular physical activity, thus yielding a healthy weight -nutrition status-; therefore, lifestyle modifications could greatly contribute to a worldwide reduction in the cancer burden.
Diet
While other foods, nutraceuticals and dietary components that have been associated with a reduced cancer risk will be mentioned, herein we present quite the opposite: foods to avoid -better said, minimize consumption- as they have been linked with increased risk of tumorigenesis.
Alcohol. Chronic binge drinking has been recognized as an important risk factor for cancer -particularly of the digestive tract- for more than 100 years [1]; recently, it has also been associated to breast, liver, colon, and rectum cancers [2]. Studies have found that even light-drinking (i.e., ≤12.5 g/day) is associated with a 7% increase in the risk, whereas heavy drinking is associated with a 52% increased risk, compared with nondrinkers or occasional alcohol drinkers [3]. Although molecular mechanisms for alcohol’s increased risk in cancer initiation and progression have not been fully elucidated, some have been proposed, for example: the metabolism of ethanol into acetaldehyde also promotes oxidative stress, which in turn, may initiate/progress carcinogenesis due to the binding of free radicals to DNA and/or proteins hence promoting mutations. In addition, alcohol can activate proinflammatory pathways associated to tumorigenesis [4]. Finally, evidence also suggests that alcohol excessive intake also modulates epigenetics as it promotes aberrant DNA methylation -most likely through decreasing the main biological methyl donor, S-adenosylmethionine (SAMe), bioavailability- [5-6].As with everything, there are two sides of a coin; regarding alcohol consumption and cancer, several observational studies have also evidenced that - opposite to excessive drinking- moderate alcohol intake (i.e., 1 or 2 glasses/day, for women and men, respectively) is associated with reduced overall morbidity and mortality. Nevertheless, it has not been established whether such health benefits are due to ethanol and/or other non-alcoholic components (e.g., polyphenols, as we will later discuss) [7].Red Meat. Several observational studies have found a possibly increased relative risk of cancer (prostate, colorectal, hepatic, and esophageal, among others) in patients with high dietary consumption of meat [8{Pham, 2014 #711, 8-10].It is worth mentioning that such association remains controversial as results have been inconsistent among studies and, moreover, there is a statistical difference when dividing “all meat” from “processed meat”. This may be explained by the fact that, with cooking and processing of meat and meat products [11], compounds like heterocyclic amines and nitrosamines and N-nitroso compounds -which exhibit carcinogen activity- are produced; moreover, smoking, grilling, and/or charcoal cookery yield pyrolysates (also carcinogenic and mutagenic activity) [12-14]. Other possible contributors to such increased risk are additives used in processed meat products, e.g., nitrites and nitrates; these have also been reported to exert genotoxicity thus carcinogen effects, mainly at the gastrointestinal level but also in lung and thyroid [15-18]. In fact, studies have reported a stronger association and higher risk for advanced prostate cancer in subjects with more frequent consumption of hamburgers, processed meat, grilled meat, and barbequed and well or very well done meat [19-21].Yet another hypothesis states that regular meat consumption promotes chances in the colonic microbiota, enhancing the colonization and predominance of Bacteroidetes. These microorganisms synthesize menaquinones -vitamin K isoprenalogues- which have been proposed as initiators of redox cycling reactions that yield superoxide and hydrogen peroxide, i.e., powerful oxygen reactive species. Moreover, additional vitamin K1 metabolites, e.g., phylloquinone, which are both obtained from either microbiome or mixed within bile acids, have also been reported to enter into a redox cycle that yields superoxide. The latter may, in turn, rapidly react and oxidize proteins and/or fatty acids, starting a chain reaction that further contributes to oxidative stress and may form active carcinogens or tumor promotors, thus, may be considered as a risk factor for carcinogenesis [22-23].Finally, meat consumption also increases fecal iron content (as meat contains it within haemoglobin). Heme iron has been proposed as a possible initiator and promoter of colon cancer as it enhances lipid peroxidation, mainly through Fenton reactions [24]. Furthermore, is has been recently proposed that intestinal microbiota could play a crucial role within iron-associated cancer pathogenesis as fecal lipoperoxidation markers (e.g., malondialdehyde) significantly decrease after antibiotic treatment. [25]Summing up, despite the fact that reports are controversial and therefore no contending evidence has linked meat to cancer risk, all investigations consent to advice that red meat intake should be limited/minimized as such food might be associated with increased risk of carcinogenesis although prospective studies and experimental research are indeed needed.High-Fat Diets. Some neoplasms, e.g., breast cancer [26], have been associated with high-fat (particularly from animal food sources) dietary patterns. Among the proposed mechanisms contributing to this phenomenon are: a) fat intake may increase endogenous estrogen concentrations, b) saturated fat may increase the risk of breast cancer by enhancing insulin resistance, c) the generation of eicosanoids, from fatty acids, as well as lipid peroxidation may be involved in the modulation of genes associated with mammary carcinogenesis [27-29]. However, fat consumption has not been proven to be associated with many other types of cancer; for example, regarding prostate cancer, studies have not found a relation between the intake of total, saturated, monounsaturated or polyunsaturated and the risk of prostate cancer [8, 30].Low-Fiber Diet. Dietary fiber intake has been associated with a reduction in the risk of colorectal cancer and adenoma, thus a low-fiber diet has been associated with an increased risk of developing these conditions. Several studies have focused on this association, including two meta-analysis that conclude that dietary fiber intake is inversely associated with the risk of colorectal adenomas and cancer: fiber has shown to reduce the risk of developing colorectal cancer by 10% for each 10g/day of fiber intake. Conversely, low dietary fiber intake (<10g/day) was associated with an 18% increased risk for colorectal cancer [31-33]. Some possible mechanisms through which fiber may reduce such cancer risk include an increase in stool bulk, dilution of fecal carcinogens within colonic lumen, decreased intestinal transit time, as well as production of short chain fatty acids by bacterial fermentation, which increase beneficial gut microbiota and induce differentiation, arrest growth, and cause apoptosis within the gastrointestinal tract [31, 32, 34].Another example is breast cancer: currently two meta-analyses have found an inverse association between soluble fiber intake and breast cancer risk; further, when dose-response analysis was performed, results revealed that breast cancer risk is significantly decreased in 7% for every 10 g/day increase in dietary fiber. This phenomena may be due to several mechanisms, e.g., dietary fiber may attenuate estrogen blood levels as a result of decreased reabsorption of those hormones (normally, conjugated estrogens are excreted within the bile and may be further reabsorbed at the intestine; however, fiber may bind to such estrogens hence preventing them from entering enterohepatic circulation, i.e., being reabsorbed). Furthermore, soluble fiber delays gastric emptying thus slows glucose absorption and attenuates postprandial hyperglycemia and consequent hyperinsulinemia, which has been proposed to be a risk for breast cancer [35].Finally, as to prostate cancer and dietary fiber intake, studies have shown conflicting evidence, ranging from a lack of association to an inverse correlation. The effect exerted by fiber can be explained through several mechanisms, including the anti-inflammatory effect of short chain fatty acids provided by fermentation of dietary fiber by the colonic microbiota, as well as an improvement in insulin resistance through a decreased carbohydrate absorption rate [36].Physical Activity
Research suggests that physical activity (PA) reduces the risk of developing cancer, helps cancer survivors to recover from the treatment, improves long-term health and could reduce the risk or recurrence [37]. In contrast, a sedentary lifestyle has been associated with a wide range of chronic diseases, including cancer and, within the latter, the association is particularly strong breast, colorectal, endometrial, and prostate neoplasms [38].
In addition to the fact that PA is negatively correlated to overweight and obesity thus reduce the inherent cancer risk of such conditions -as discussed in the next section-, the practice of exercise increases the expression and activity of cellular growth and proliferation participating molecules, including sirtuins (SIRTs), hence play an important role in the prevention. SIRTs are a family of NAD+ dependent histone deacetylases which are activated by stress -in this case, manifested as energy shortage from utilization during PA- and have key functions such as cellular defense and repairing activities. SIRT1 is localized in nucleus and cytosol and modulates, among others, neurodegeneration, cell death, gene expression and tumorigenesis. Within the cytosol, SIRT2 is involved in gene expression regulation, cell cycle regulation, DNA damage response, neurodegeneration and cancer. In the mitochondrial inner membrane, SIRT3 participates in the cellular response to oxidative stress, cell death, and tumor suppression positively influencing genomic stability. SIRT6 is involved in DNA repair and genome stability [39]. Moreover SIRT1 modulates levels of the enzyme Suv39H1, which is involved in the maintaining of the structure of heterochromatin during the response to the oxidative stress. This implies an increase in the rate of renewal of heterochromatin, which implies greater protection of the genome [40].
Nutritional Status
Obesity results from an imbalance between the two aforementioned lifestyle actors: excessive and inadequate diet plus insufficient physical activity. The World Health Organization (WHO) defines obesity as a chronic disease characterized by the presence of excessive fat mass to a level that may impair health. It is widely recognized that such condition is a leading risk for worldwide mortality as it is frequently associated with other diseases (i.e., comorbidities), commonly cardiometabolic alterations -e.g., type 2 diabetes mellitus, dyslipidemias, and coronary disease, among others- but also various malignancies (e.g., ovarian, esophageal, breast, large bowel, pancreatic, lymphomas, etc.) have been attributed to obesity [41, 42]. However, the links between nutritional status and the risk of cancer are numerous, intricate, and frequently interrelated, and so they are not yet fully elucidated. In the following lines, we will briefly mention some of these pathways.
Adipose tissue is now recognized as a metabolically active organ that, when in excess, it promotes macrophage infiltration and thus the release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα). Among other deleterious effects, the latter ultimately leads to insulin resistance (IR) [43, 44] which, in turn, increases pancreatic secretion of the hormone, resulting in hyperinsulinemia. Some studies have reported the association between increased insulinemia and the risk of developing several cancers (e.g., pancreatic, colon, prostate, breast, renal, endometrial). This epidemiologic phenomenon may be explained by the fact that insulin binding to either its own receptor or to the insulin-like growth factor (IGF) receptor, activates signaling cascades (e.g., the mitogen-activated protein kinase -MAPK- pathway) that culminates in mitogenic activity and anti-apoptotic mechanisms thus may potentiate cancer cells proliferation and tumor progression [45-47]. In fact, within the preclinical scenario, blocking such receptors and/or attenuating hyperinsulinemia has been reported to reduce tumor growth and metastasis [48]. For its side, in the clinical setting, a recent pilot trial assessed dietary restriction of carbohydrates in advanced cancer patients, with the objective of decreasing insulin secretion [49]; however, no certain conclusions can been drawn from such small trial.
But high insulin levels may exert pro-carcinogenic effects not only by the aforementioned molecular pathways but also by mediating angiogenesis as the hormone induces vascular growth factors (e.g., vascular endothelium growth factor, VEFG) thus enhancing tumoral blood supply and, therefore, proliferation and growth [50].
Yet another deregulated hormone in obesity is estrogen. The latter has been associated with cancer; the pathophysiology underlying such phenomenon relies on the fact that the binding of estrogen to its alpha-receptor (ERα) stimulates cellular proliferation and inhibits apoptosis; moreover, it also induces VEFG thus enhances angiogenesis [50].
Last but not least within the endocrine aspect linking obesity and cancer, two hormones have also been identified as actors in such relationship: leptin and adiponectin. Both adipocytokines, such hormones exhibit regulating cell proliferation but in certainly opposing ways: preclinical studies have shown that the activation of one of the leptin receptors (i.e., the Rb type) stimulates cellular proliferation and survival in some classes of cancerous cells, whereas adiponectin pathways stimulate apoptosis and inhibit cancer growth [50]. Moreover, significant associations have been reported in epidemiological studies: as obesity increases, serum leptin increases and adiponectin levels decrease; simultaneously, cancer risk is augmented [51-55].
Finally and briefly, obesity results is a condition of chronic low-grade inflammation due to the aforementioned secretion of certain cytokines, including TNFα, but also others like nuclear factor kappa b (NFκB), interleukins 1 and 6 (IL-1β, IL-6), monocyte chemoattractant protein (MCP) and C-reactive protein (CRP). All of these participate in the modulation of inflammatory pathways leading to both initiation and progression of the carcinogenic process [42, 56-58].
Nutritional approaches, functional foods and nutraceuticals: molecular pathways, scientific evidence and potential applications within cancer therapy
As evidenced in the previous sections, food/nutrition and cancer are intimately linked not only during the developmental stage of the disease but also during its promotion and progression. Hence, nutrition therapy during cancer therapy should be considered not only oriented to avoiding malnourishment and managing symptoms (either from the disease or from the antineoplastic treatment), but also as a concomitant and coadjuvant oncologic approach considering that diet and nutraceuticals also modulate molecular pathways involved in the carcinogenic process.
Energy Restriction
This approach -which has been around for almost a century- has traditionally been aimed towards longevity; results have shown that both in the preclinical and the clinical scenario, subjects with lower caloric intake have a longer lifespan. Regarding the Oncology field, emerging evidence has shown that continuous energy restriction is associated with protective effects on carcinogenesis; although intermittent caloric restrains have shown similar trends, data is yet inconclusive [59, 60].
Possible mechanisms for elucidating such beneficial effects include the “obligated” shift from glucose as the main source of energy for cancer cells towards ketone bodies -resulting from beta oxidation- since carbohydrate is no longer available. Such shift permits the survival of normal cells whilst inhibiting the neoplasm’s growth due to the fact that the latter cells do not exhibit such evolutionary adaptation capacity [61]; hence cancer cells are quite vulnerable to energy restriction.
In fact, drugs that are able to activate and thus mimic the energy restriction pathways have recently been used within cancer therapeutics. For example, thiazolidinediones -originally developed for treating type 2 diabetes mellitus- are agonists of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) thus promote the activity of several proteins (including sirtuins and AMP-activated kinase) that interplay in different metabolic pathways that converge in the modulation of apoptosis, endoplasmic reticulum stress, and cell death [62-64]. In tandem with these mechanisms, recent publications have reported that dietary energy deprivation inhibits the activity of cancer promoters, including the oncogene Raf-1 and the subsequent MAPK/ERK-1 pathway [65].
Yet additional mechanisms that might be involved in the antitumor effects of caloric restriction (CR) are those correspondent to the increased expression of Sir2, a member of the Above mentioned SIRTs family [66].
Nevertheless, it is indeed difficult to implement chronic energy -dietary- restriction as part of the human antineoplastic treatment as cancer patients are often malnourished and cancer cachexia is, by itself, an additional negative prognostic condition for overall survival and complications incidence thus restricting energy may be more deleterious than beneficial in such particular conditions [67]. This fact leaves the modulation of energy balance to be more attractive as a preventive -rather that therapeutic- strategy within cancer research. Corresponding epidemiologic evidence has shown that, actually, obesity (i.e., a condition resulting from a positive energy balance) increases the risk of developing and worsens several malignancies, including colon, gynecologic (e.g., breast and endometrial), hepatic, gallbladder, and even hematologic (e.g., leukemia) cancers [68, 69].
The potential mechanisms underlying these two conditions -i.e., cancer and obesity- have been mentioned in the first part of this chapter and include mainly hormonal disruptions that enhance the carcinogenic process: a chronic exposure to a CR regimen results in reduced levels of growth factors, insulin, IGF-1, leptin:adiponectin ratio, and VEGF. Such decreased levels, in turn, lead to a decline in the PI3K/Akt (phosphoionositide 3-kinase) and mTOR (mammalian target of rapamycin) pathways; lesser inflammation by downregulating NFκB and cyclooxygenase-2 (COX-2) [70, 71]. The PI3K/Akt pathway is one of the most commonly activated pathways in epithelial cancers. This pathway regulates cellular survival, proliferation, protein translation, and metabolism. Akt regulates the mTOR which regulates cell growth and proliferation. Increase in mTOR is usual in tumors and is decreased with CR and its activation is inhibited with the increase of AMPK during low nutrient conditions. Adiponectin has anti-cancer effects because increases insulin sensitivity so decreases the insulin/IGF-1 and mTOR signaling by activating AMPK and also reduces proinflammatory cytokine expression by inhibiting NFκB. CR decreases systemic and tissue VEGF which is produced by adipocytes and tumor cells. A growing tumor has need for nutrients and so the formation of new vessels is required, this is why these cells produce VEGF [70, 71].
Omega-3 Fatty Acids [72-83]
The most important omega-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) involved in human nutrition and cancer are docosahexaenoic acid (DHA; 22:6n-3), eicosapentaenoic acid (EPA; 20:5n-3), and docosapentaenoic acid (DPA; 22:5n-3). The intake of these fatty acids is essential to human health, because its endogenous production is insufficient; hence it is recommended to regularly consume (i.e., ≥2 times/week) rich sources of EPA and DHA such as cold-water oily fish, e.g., salmon, sardines, mackerel, etc., or fish oil supplements.
In vitro assays regarding the effects of DHA and/or EPA on apoptosis, in different cancer cell lines such as breast, colon, lung, prostate, etc. have found that these PUFAs promote apoptosis of such cancer cell lines, while not affecting healthy tissues. This effect could be attributed to the modulation of certain pathways present -or altered- only in cancer cells.
PUFAs may also enhance cancerous cell death through other receptors and enzymes, such as the Bcl-2 family, which has been associated to tumor anti-apoptotic mechanisms. In colon cancer cell cultures, n-3 PUFAs have shown decrease the expression of Bcl-2 and consequently increase apoptosis. In addition, other studies involving apoptosis mechanisms have shown an upregulation of caspases 3, 8 and 9 in cell cultures when incubated with n-3 PUFAs.
Yet another phenomenon involved in carcinogenesis is inflammation. Arachidonic Acid (AA), an n-6 PUFA, acts as substrate for cyclooxygenase (COX) 1 and 2, and lipoxygenase (LOX) 5, 12 and 15, which produce eicosanoids, such as prostaglandins, leucotrienes, and thromboxanes, involved in the inflammatory response. n-3 PUFAs are also substrates for COX and LOX, however, n-3 PUFAs’ metabolites exert less pro-inflammatory activity than those of AA (i.e., COX-2 metabolizes EPA into PGE3, whereas AA into PGE2, which has been associated with an increase in tumor progression). Furthermore, n-6 PUFAs-derived eicosanoids promote cell growth, angiogenesis, and invasion in cancer cells; this may be -partly- explained n-6 PUFA metabolites produced by COX-2 have been associated with an increased expression of the Bcl family, particularly Bcl-2, leading to a decrease in apoptosis.
Furthermore, n-3 PUFAs’ metabolism by LOX yields bioactive molecules that, in turn, activate transcription factors such as the PPARs family more efficiently than its precursors (e.g., LOX metabolizes DHA into 7-hydroxy and 17-hydroxy DHA, a more potent PPAR-activator than DHA itself). Peroxisome Proliferator-Activated Receptors (PPARs) have been reported to exhibit anticarcinogenic activity, for example, PPARα is associated with cell differentiation and anti-proliferative effects; PPARγ is a target for DHA, and may bind to the promoter of p53 to stimulate its expression. The activation of PPARγ by EPA may lead to an increased transcription of Syndecan-1, a heparin sulfate proteoglycan associated with apoptosis induction.
Other pathways in which n-3 PUFAs, might exert an anti-cancer effect include different receptor related growth factors. For example, in vitro studies in breast cancer cells have shown that EPA and DHA decrease the expression and activity of the epidermal growth factor receptor (EGFR), leading to a decrease in the tumor growth. Other in vitro studies have shown that n-3 PUFAs decrease angiogenesis as they suppress endothelial cell proliferation induced by the vascular endothelial growth factor (VEGF). The Insulin-Like Growth Factor (IGF) family is related to the pathogenesis of cancer; experimental studies have shown that n-3 PUFAs exert an effect on pathways related to the IGF family, contributing to a decrease in tumor growth and proliferation.
Within human subjects, observational and retrospective studies have effectively demonstrated that dietary intake of n-3 PUFAs, particularly EPA, is related with a significant risk reduction for presenting colorectal, breast, lung, and skin cancers -and others-; although current experimental evidence is inconsistent among cancer types, treatment protocols, doses, and overall endpoints. Hence no sufficient evidence supports the recommendation of specific dosages from either dietary sources or supplemental presentations.
Sulforaphane
Sulforaphane is an isothiocyanate derived from glucoraphanin, the main glucosinolate in cruciferous plants (e.g., broccoli, cabbages, cauliflower, kale, collard greens, mustard seeds, turnips, and Brussel sprouts). The highest content among the aforementioned is found in broccoli, presenting 119.4 mg/100g) through the hydrolytic action of myrosinase [84].
Some in vitro and in vivo preclinical studies of breast cancer stem cells have suggested that sulforaphane may be able to modulate cancer progression by downregulating by targeting the Wnt/β-catenin pathway and thus eliminating stem cancer cells [85]. Moreover, the anticancer effects of sulforaphane also include epigenetics as it has been proven to inhibit histone deacetylases which, in turn, result in a facilitated binding of repressor proteins that, consequently, downregulate certain proteins that participate in cancer development and progression, e.g., telomerase reverse transcriptase (TERT) [86].
Yet another proposed mechanism for sulforaphane consists in the inhibition of nuclear factor kappaB (NFkB) [87]; this results in an enhanced response to apoptotic signaling in otherwise resistant cancer cells [79]. This effect is synergistically enhanced as the nutraceutical activates and induces the expression of proapoptotic proteins including caspase-3 and -9, Bim, Bax, and Bak, concomitantly decreasing the expression of antiapoptotic molecules such as Bcl-2 and Mcl-1 [88].
Uridine 5´-diphospho (UDP) -glucuronosyltransferase (UGT) 1A is another mechanism potentially responsible for the chemopreventive activity of sulphoraphane. UGT is the representative enzyme in phase II reactions; it conjugates endogenous and exogenous substances with a β-glucuronic acid, thus yielding a more water-soluble soluble molecule that is therefore easily excreted. This way, the exposure to carcinogens is reduced hence so is the risk for developing cancer [89].
On the opposite side, other research groups have shown that sulforaphane induces nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor involved in the activation of endogenous cell defense mechanisms through the nutracetic’s binding to Kelch-like ECH-associated protein 1 (Keap1), a key protein that represses Nrf2 by facilitating the ubiquitination and subsequent proteolysis of the latter. Hence, as sulforaphane inhibits Keap1 function, transcriptional activity of Nrf2 is enhanced and cytoprotective action from environmental carcinogens reduces health risk in exposed individuals [90]. However, the overexpression of such molecule results in an increased resistance of cancer cells to antineoplastic agents thereby such nutraceutical might exert a negative role during radio- and chemotherapy treatment [91].
Despite the aforementioned evidence -and the fact that very few clinical trials [84] have been performed hence more studies are indeed needed- crucifers are not usually included in the average diet at quantities that may exert significant changes in health or disease [92]. Moreover, commercial supplements of sulforaphane are not always effective as both glucoraphanin and myrosinase must be preset in order to yield the active compound and thus be able to be bioactive [93, 94]. Finally, in terms of pharmacokinetics, sulforaphane is rapidly absorbed -peaking in plasma within 1.5 hours- and an excretion half-life of about 2.5 hours; however, these parameters change if the nutraceutical comes from cooked cruciferous [95]. Therefore, research has yet a long way to go before dietary recommendations and functional/nutraceutical interventions are included within cancer treatment and/or prevention [96].
Lycopene
Lycopene is bright red colored member of the carotene-carotenoid family that participates as an intermediate in the biosynthesis of other carotenoids (e.g., beta-carotene and zeaxanthin) [88]. As carotenoids are found in photosynthetic plants, lycopene dietary sources include tomato, watermelon, pink grapefruit juice, papaya, apricots, pink guava, and gac; although the latter has the highest content of lycopene, due to its low accessibility worldwide, tomato is generally considered as the vegetable food with the most content and, in fact, its consumption accounts for more than three-quarters of the general dietary intake.
“The anticancer activity of lycopene has been demonstrated in both in vitro and in vivo tumor models as well as in humans. The proposed mechanisms for the anticancer effect of lycopene involve ROS scavenging (i.e., antioxidant activity), up-regulation of detoxification systems through the induction of phase II enzymes, interference with cell proliferation, induction of gap-junctional communication, inhibition of cell-cycle progression, and modulation of signal transduction pathways” [97].
Nevertheless, the role of lycopene and other vitamin E metabolites within cancer prevention/treatment remains considerably controversial as different doses have not only shown no-effect but, some, an increased risk of presenting cancer, e.g., the VITAL, SELECT, and ATBC clinical trials [98-102].
Antioxidants
Antioxidants, as the name states, are species that when present, inhibit or delay the oxidation of other molecules caused by reactive oxygen species (ROS) and/or other free radicals [103]. ROS in low doses are beneficial for normal physiological actions but in high doses have deleterious effects as they are able to oxidize other components and start a chain reaction that ultimately damage proteins and genetic material thus promote both initiation and progression of the carcinogenic process [90]. The principal dietary antioxidants are “vitamins C and E, zinc, selenium, carotenoids (β-carotene, lycopene, lutein, zeaxanthin), phenolic acids (chlorogenic acids, gallic acid, caffeic acid), flavonols (proanthocyanidins and catechins), anthocyanidins (cyaniding and pelagonidin), isoflavones (genistein, daidzein and glycitein), flavones (naringenin, eriodictyol and hesperetin), and flavones (luteolin and apigenin)” [104].
In theory, is seems fair to assume that antioxidant consumption should decrease overall cancer risk and cancer-associated mortality [105-109]. However, the issue remains controversial -and, may we say, nowadays the evidence points towards an opposite way- as experimental studies have revealed conflicting results, e.g., no reduced risk in the incidence of different cancers [92], or in long-term cancer-associated mortality [93]. Overall, clinical trials have found (in the best scenario) no beneficial anticarcinogenic effect [94]; moreover, some other studies have proven that, in fact, high-dose antioxidant supplementation may be harmful as the relation of supplementation in preventing cancer is a U-shaped curve [95, 96] and a recent preclinical report showed that some antioxidants resulted in a significant (3x) increase not only in tumor number, but in such tumors’ aggressiveness because antioxidants decreased the DNA damage “actually needed” to releases the tumor-suppressing protein p53 [110].
Polyphenols (Brief Examples)
Polyphenols are phenylalanine plant-derived metabolites that subdivide in groups according to the number of phenol rings they present and - also - to the elements that bind such rings. The main classes include phenolic acids, flavonoids, stilbenes and lignans [111].
Although polyphenols have traditionally been considered as strong antioxidants (which they actually are), evidence suggests that the primary means of action of such molecules could be through modulation of signal transduction systems and gene expression, together with downregulation of the inflammatory pathway.
Lignans. These have been reported to exhibit anti-estrogenic, anti-angiogenic, anti-oxidant, and pro-apoptotic activities. Because lignans possess a structural similarity to 17-ß-estradiol, they may influence estrogen related pathways; e.g., enterolactone may act as a weak estrogen agonist or anti-estrogen hence decrease the risk of estrogen-associated neoplasias including those of the breast, ovaries, and endometrium, due to the fact estrogen receptors modulate signaling pathways involved in cell proliferation and apoptosis. Furthermore, the antioxidant effect of lignans has been demonstrated in lipid and aqueous in vitro models: results show a preserved vitamin E status, as well as control of lipid peroxidation. Research using cell cultures has shown that lignans also posses the ability to inhibit cell proliferation, as well as decrease tumor number, size, volume and suppress tumor growth rate [112, 113].Curcumin. It is the best known linear diphenylheptanoid (i.e., curcuminoids) and the most abundant in turmeric (Curcuma longa). This polyphenol is one of the most studied within cancer research; the - probable - first report was conducted almost 30 years ago and consisted in the application of topical curcumin in cancerous lesions: patients reported a significant improvement in diverse symptoms such as itching and pain [114].Nowadays, curcumin research has yielded promising results, including the inhibition of inflammatory pathways (e.g., TNFα, NFκB, IL-6, COX-2, PCR and prostaglandin E2) together with adhesion molecules, growth factors, cyclins, apoptotic proteins, and the induction of p27 and p53, both in in vitro models of different cancers and within the clinical scenario [115-118].As other polyphenols, curcumin is an attractive nutraceutical since it is usually well-tolerated and few side-effects, such as mild nausea and diarrhea, have been reported (usually when large doses, i.e., >5g/day, are used) [115, 119]. Although the main issue remains its poor bioavailability due to low absorption and rapid metabolism and systemic elimination, benefits from curcumin/turmeric supplementation in cancer therapy are certainly promising [120].Resveratrol. It is the most representative stilbene; it is found in grapes, soy, peanuts, and other berries. Resveratrol has been reported to exhibit “anticancer properties against a wide variety of tumors, including lymphoid and myeloid cancers, multiple myeloma, and cancers of the breast, prostate, stomach, colon, and pancreas. Such effects are mediated through cell-cycle arrest; induction of apoptosis via Fas/CD95 and PI3K/AKT pathways with subsequent induction of FOXO transcriptional activity, ceramide activation, tubulin polymerization; up-regulation of p21 p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL, and cellular inhibitor of apoptosis proteins; activation of caspases; suppression of nitric oxide synthase; suppression of transcription factors such as NFκB; inhibition of COX-2 and lipoxygenase; suppression of adhesion and angiogenesis molecules (including VEGF and VCAM), invasion, and metastasis” [121, 122].Moreover, resveratrol has been reported to sensitize tumor cells and thus enhance the effect of chemotherapeutic drugs such as doxorubicin and radiation therapy while not affecting normal cells. Such phenomenon is modulated via the death receptor ligand (TRAIL), whose potentiated activation with the stilbene results in the induction of apoptosis [123].Some reports suggest that daily oral doses of resveratrol at 0.5-1 g elicit anti-carcinogenic effects; however, further clinical evaluation as a potential anticancer agent is yet needed to emit accurate dietary and nutraceutical recommendations [124].Microbiota [125-134]
The microbiome is composed of the microbial cells present in the human body called microbiota, as well as their collective genomes. It is a recently studied topic involved in multiple diseases that range from autoimmune diseases, irritable bowel disease, metabolic syndrome, as well as cancer. In the latter the microbiota can increase or decrease cancer susceptibility through several mechanisms; microbiota changes have been associated with certain types of cancer such as oral squamous cell carcinoma, breast cancer, pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and colorectal cancer, possibly the most studied type of cancer affected by the gut microbiota. Different experimental studies have observed tumor-promoting effects by bacterial microbiota, and to a lesser extent antitumor effects; specific bacterial components act as agonists for Toll-like receptors (TLR), and NOD-like receptors (NLR), these have been associated with the anti-tumor effects, it has been observed that stimulation of these receptors could lead to antitumor immune responses, however the stimulation triggered by the microbiota is insufficient for the activation required for antitumor immune responses, and instead leads to a low-grad chronic inflammation. Alterations in the microbiota composition, i.e., dysbiosis, is a stat resulting from an unbalanced proportion of harmful vs healthy gut bacteria; such dysbiotic environments may promote hepatocellular carcinoma through microorganism associated molecular patterns (MAMPs) as well as bacterial metabolites, it has been shown that germ free states decrease the development of hepatocellular carcinoma in animal models; MAMPs exerting an inflammatory effect could promote pancreatic cancer. Different mechanisms control the symbiotic state of homeostasis between the host and the microbiota; anatomical barriers are probably the most important, in the gut these barriers are composed on an epithelial lining, as well as a mucous layer, and the presence of gut-associated lymphoid tissue (GALT), which secretes IgA, another mechanism involved in the homeostasis of the gut microbiota. The development of cancer is associated with failure in barrier protection (i.e., disruption of gap junctions) and a dysbiotic state; the latter can be triggered by changes in dietary patterns, inflammation, infections, innate immune responses, etc. Experimental studies have shown that MAMPs and TLR are involved in carcinogenesis, activation of TLR4 by bacterial lipopolysaccharide promotes liver, colon, pancreas and skin cancer. TLR signal promotion induces several pathways involved in survival and inflammation, such as the NF-κB and STAT3; TLRs could also be associated with tumor proliferation through the release of mitogens such as epiregulin (which stimulates the extracelluar-signal-regulated kinase pathway, encouraging tumor proliferation), amphiregulin and hepatocyte growth factor by fibroblasts. Stimulation of the immune system is not the only way in which the microbiota exerts a promoting effect; bacterial derived genotoxins have been associated with the promotion of cancer, cyclomodulins are genotoxic virulence factors, some of them include cytolethal distending toxin, cytotoxic necrotizing factor 1, colibactin, B. fragilis enterotoxin, etc. which lead to DNA damage, and thus are implied in tumorigenesis; other bacterial metabolites lead to an oxidative stress leading to a genomic instability, examples of these metabolites include superoxide and hydrogen sulphide. On the other hand, short-chain fatty acids, such as butyrate and propionate, are product of the fermentation of certain substrates by the colonic microbiota, these short chain fatty acids, have been associated in the protection of colon and hepatocellular carcinoma; butyrate has antitumorigenic and antiproliferative effects due to its regulation of genes related with cell proliferation and induction of apoptosis via histone deacetylase inhibition. The gut microbiota is also responsible for the metabolism of certain polyphenols, such as lignans into their active mammalian form.
Probiotics are live microbial food ingredients that confer beneficial health effects to the host upon ingestion in adequate amounts; certain probiotics have been studied in the prevention of cancer, such as lactic acid bacteria (LAB), which include Lactobacillus spp, and Bifidobacterum spp. LAB can exert their antitumor effects in different manners, such as by uptaking nitritates and reducing the levels of secondary bile salts; LAB absorb herterocyclic amines, which have been proposed as carcinogens. An increased activity of antioxidative enzymes is another proposed effect of LAB, some of these enzymes include glutathione reductase, and glutathione peroxidase. Certain probiotics such as L. acidophilus and L. casei can decrease the levels of certain enzymes associated with carcinogenesis, such as glycosidase, ß-glucuronidase, azoreductase and nitroreductase, these enzymes transform precarinogens into active carcinogens. Lactobacillus rhamonsus GG (LGG) has been shown to be a powerful scavenger of reactive oxygen species, as well as an inhibitor of lipid peroxidation in vitro Furthermore certain LAB have shown to enhance the immune system of their host, by stimulating the secretion and production of IgA; L. casei and LGG can affect cytokine production and enhance phagocytosis of pathogens. Lactobacillus casei Shirota (LcS) and its anti-cancer effects have been widely studied, LcS has shown to exert an inhibition of carcinogenesis through regulation of the immune system of its host in an animal model, possibly by activating natural killer cells; in animal models the inhibition of IL-6 mediated inflammatory response in the colonic mucosa by LcS was associated with a suppression in carcinogenesis; other effects of LcS include the excretion of carcinogens by adsorbing them. In cancer cell cultures, L. reuteri suppressed the activation of NF-kB, as well as regulated pro-apoptotic mitogen-activated protein kinase signaling.
Prebiotics are nondigestible food ingredients that selectively stimulate the growth and/or activity of gut bacteria, improving host health; probiotics have been used to promote a eubiotic state. Certain polyphenols have been studied as prebiotics, such as ellagic acid, which is metabolized by colonic microbiota into urolithins, as well as daidzein which is metabolized into equol, and as previously mentioned, lignans. However, the most widely studied prebiotic remains to be fiber. Fiber is fermented by the gut microbiota into short chain fatty acids, which stimulate the growth of colonocytes and inhibits the growth of colorectal cancer cell lines, this effect is possibly due to the fact that cancerous colonocytes upregulate glucose intake, which leads to a decrease in the metabolism of butyrate and thus, to its accumulation in the nucleus, acting as a histone deacetylase inhibitor, and increasing the transcription of genes related to apoptosis and cell differentiation; butyrate might also normalize the recruitment of dendritic cells in the gut. Furthermore, an in vitro study observed that short chain fatty acids were capable of improving intestinal tight junction integrity. However, the strongest effects in the use of prebiotics have been demonstrated when administered in combination with probiotics, this combination is termed synbiotic. A clinical trial evaluated the supplementation with the symbiotic mixture of LGG, B. lactis Bb12 and fructans in patients with resected colonic polyps or cancer; this supplementation resulted in a significant reduction in FNA damage in the colonic mucosa.
Conclusion
In the previous sections, we have attempted to briefly revise some nutraceuticals that have been associated with cancer prevention/treatment. These molecules, as their definition implies and has been described, are derived and/or isolated from certain foods. However, in the day-to-day life, such consumption is not frequent and -in many cases- it may be nearly impossible to achieve. Instead, whole foods are ingested and these contain not only one, but rather several nutraceuticals that could exert beneficial anticarcinogenic effects (as described before), thus are considered as functional foods. An example of these is flaxseed.
Flaxseed (Linum usitatissimum) is an oilseed crop that has been used as a food, textile fiber, and as a part of medical therapies since 5000 B.C.; in fact, its scientific name means “very useful”. Flaxseed has been recognized as a functional food, due to its high content of omega-3 fatty acids, fiber, and phenolic compounds (i.e., lignans, ferulic acid, p-coumaric acid, cholorogenic acid, gallic acid, caffeic acid, phenylpropanoids, and tannis). Other micronutrients present in flaxseed include vitamin E in the form of tocopherols, predominantly γ- and α-tocopherol, as well as the minerals calcium, magnesium and phosphorus [135, 136]. Moreover, flaxseed is rich in omega-3 fatty acids, particularly ALA which -as mentioned in afore sections- has been suggested to exert anti-cancer effects through the regulation of transcription factors, such as PPARs, alteration in the cell membrane phospholipid and fatty acid composition, as well as the downstream effects on eicosanoid biosynthesis and lipid peroxidation.
What we attempt to show with the flaxseed example is that, within everyday cancer prevention and therapeutics, there are certainly individual molecules that exhibit important potentially beneficial effects; however, evidence is yet inconsistent and/or insufficient to issue real recommendations. Moreover, such molecules -nutraceuticals- are part of more complex foods thus interactions (either beneficial or deleterious) with other molecules may present hence may alter the desired effect. The mechanisms underlying these effects are currently under extensive investigation and prominently feature the actions of isolated nutraceuticals and/or functional foods, with exciting and promising results. However, conclusive evidence on salutary effects require well-designed, controlled, long-range clinical studies, encompassing hundreds of patients, focused on “hard” endpoints such as cancer mortality including relevant surrogate points.
However, what evidence has effectively shown is that a healthy lifestyle including correct diet and physical activity, result in a nutritional status that is not associated towards cancer risk and, in addition, offers an improved prognosis in those patients already diagnosed.
ACKNOWLEGDEMENTS
Declared none.
CONFLICT OF INTEREST
The authors have no conflict of interests to declare.
