Phytochemicals and Cancer

Phytochemicals and Cancer

The phytochemical compounds found in plants are responsible for their colour, taste, and aroma of many foods. Over and above these attributes, emerging evidence suggests that they protect us from environmental and ingested carcinogens by arming antioxidant enzymes, enhancing DNA repair pathways, reducing chronic inflammation, and directly affecting the biological processes that underlie the fundamental hallmarks of cancer progression and metastasis. It is not a surprise, then, that the World Cancer Research Fund (WCRF) and other academic bodies report that individuals eating phytochemical-rich foods have a lower risk of cancer or relapse after treatments. The debate lies in whether concentrating these into nutritional supplements or topical creams can boost their health attributes without causing significant adverse effects. One notable randomised controlled trial has demonstrated benefits of a polyphenol rich a nutritional supplement for men with prostate cancer, another Randomised Controlled Trial (RCT) used a polyphenolic rich topical balm to prevent distressing chemotherapy induced nail loss but, considering their potential benefits there is a shortage of robust RCT’s. This page review highlights significant RCT’s relating to cancer, their probably mechanisms of action and scope for future research.

An increasing number of well-conducted studies are linking higher intake of phytochemical-rich foods with lower risks of chronic disorders ranging from arthritis to type 2 diabetes mellitus (T2DM), as well as a lower risk of cancer and its relapse after initial treatments (Block et al. 1992; WCRF/AICR 2007; Key 2011). Of the numerous subcategories of phytochemicals, one of the largest and most well-researched groups is the poly phenols (Table 1). The average total dietary intake of polyphenols is reported to be over 1g per day, which is up to ten times higher than that of all other classes of phytochemicals (Scalbert et al. 2005). Laboratory experiments have elucidated several anticancer mechanisms of action for phytochemicals, which might explain their benefits for patients both before and after cancer. Cohort studies correlating dietary patterns with disease outcomes provide useful insights but scientific credibility is diluted by multiple causative factors in food and other lifestyle factors. Prospective clinical studies increasing dietary intake of certain rich foods are difficult to design and control so most studies evaluate the pros and cons of concentrating phytochemicals into nutritional supplements in an attempt to further harness their health benefits. Nutritional supplements appear to be popular with cancer patients despite most of them not undergoing scientific evaluation (Uzzo et al. 2004; Bauer et al. 2012).This review provides up-to-date information to aid communication between patients and healthcare providers on the rationale, benefits, and risks of increasing intake of phytochemical-rich foods and supplements.

Evidence for a link between phytochemicals and reduced cancer risk

Most of the evidence for the benefits of phytochemicals in cancer prevention stems from well-conducted cohort studies which have linked a higher intake of phytochemical-rich foods, such as vegetables, fruit, legumes, nuts, herbs, and spices, with a lower incidence of cancer (Block et al. 1992; Key 2011). Although not all studies confirm this association (ref) or the more relevant beneficial components of foods many more do. Of note, higher intake of carotenoids, found in leafy green vegetables and carrots, has been observed to have a significant dose-response relationship with reduced breast cancer risk in a meta-analysis pooling data from prospective cohort studies (Hu et al. 2012). Studies based on questionnaires assessing intake of phytochemical-rich foods and serum levels of biomarkers have also demonstrated associations between high carotenoid intake and lower risks of ovarian and pancreatic cancers(Tung et al. 2005; Li et al. 2011; Banim et al. 2012). Intake of cruciferous vegetables such as cabbage, cauliflower, Brussel sprouts, radishes, and broccoli have been associated with a lower prostate cancer risk(Joseph et al. 2004), as have foods rich in isoflavones such as pulses and soy products (Park et al. 2008, Yan &Spitznagel 2009; van Die et al. 2014), and lycopene-rich colourful fruits and tomatoes (Giovannucci et al. 2002).Foods with abundant levels of flavonoids such as oonions, rich in quercetin, have been associated in particular with a reducedincidence of cancers arising in the lung, especially among smokers(Knekt et al. 1997; Le Marchand et al. 2000). The anthoxanthins in dark chocolate have been reported to be associated with a lower risk of colon cancer (Rodríguez-Ramiro et al. 2011),and evidence indicates that higher green tea intake lowers the risk of breast, prostate, ovarian, and oesophageal cancers, particularly among smokers and alcoholics (Wu et al. 2004; Sun et al. 2007). Finally, higher coffee intake has been shown to be associated with reduced risks of both non-melanoma skin cancers and melanoma,even after controlling for confounding factors such as ultraviolet radiation exposure, body mass index, age, sex, physical activity, alcohol intake, and smoking history(Song et al. 2012; Loftfield et al. 2015).

Phytochemicals and Reduced Cancer Recurrence

A number of studies have demonstrated that the benefits of consuming phytochemical-rich foods do not stop after a diagnosis of cancer. For example, breast cancer survivors who regularly consumed more than the government-recommended five portions of fruit and vegetables a day and participated in regular physical activity had a significantly lower risk of breast cancer recurrence than those who did not(Pierce et al. 2007a; Pierce et al. 2007b). In another study, women with breast cancer who had the highest serum lignan levels, reflecting good intake of legumes, cereals, cruciferous vegetables, and soy, were reported to have better overall survival than those with the lowest levels (Buck et al. 2011). Alignan and poly phenol-rich diet has also been associated with a lower colorectal cancer relapse rate (Zhu et al. 2013).

The Shanghai Breast Cancer Survival Study, a large cohort study of 5,042 breast cancer survivors in China, demonstrated that women with the highest intake of the phytoestrogenic polyphenols isoflavone and flavanone, found in soya and other beans, had a significantly decreased risk of breast cancer recurrence and death from any cause compared to those with the lowest intake at a median follow-up of 4 years (Boyapati et al. 2005; Shu et al.2009).Similar findings have been observed for high intake of green tea after breast cancer (Ogunleye et al. 2010) and colorectal cancer (Zhu et al. 2013). High intake of green tea extract in a phase II trial of 42 chronic lymphocytic leukaemia patients was reported to produce a sustained, clinically significant decrease in the abnormal absolute lymphocyte count in 30% of patients (Shanafelt et al.2013). Providing supplements of the phytochemicals rich in green tea to men with prostate cancer has been associated with a reduction in levels of serum prostate-specific antigen (PSA), a marker of prostate gland disease used to monitor prostate cancer (McLarty et al. 2009). A slowing of PSA progression has similarly been observed in other interventional studies of phytochemical-rich foods for prostate cancer, most not abley a randomised controlled trial (RCT) studying an intensive lifestyle program intervention that included a vegan diet supplemented with phytochemical-rich soy products(Ornish et al. 2005),and a phase II clinical trial of pomegranate juice (8 ounces/day) (Pantuck et al. 2006).

Individuals who have been treated for squamous cell carcinoma (SCC) of the skin have a high risk of developing further skin lesions due to ongoing sun damage. A prospective study conducted in an Australian community reported that the highest levels of dietary intake of lutein and zeaxanthin-rich food softer an initial diagnosis of SCC, such as leafy green and yellow vegetables, were associated with a significantly reduced incidence of new cancer formation compared with the lowest levels of intake (Heinen et al. 2007).

A number of other studies evaluating the impact of high intake of dietary phytochemicals after cancer diagnosis are currently underway, including the UK’s DietCompLyf prospective cohort study, which is measuring serum polyphenol levels and recording dietary patterns of 3,159 women treated for breast cancer (Swann et al. 2013).

The Anticancer Mechanisms of Phytochemicals

The biochemical mechanisms through which phytochemicals exert their influence on cancer pathways are wide-ranging and still being explored. In terms of cancer prevention, a commonly cited mechanism is the direct antioxidant activity of phytochemicals, elicited through direct free radical absorption. The ability of phytochemicals to protect DNA from ingested or environmental carcinogens, however, is likely to be mainly indirect, via their enhancement of the natural antioxidant enzymes and pathways in the body. Laboratory studies have shown that phytochemicals activate Nrf2, a transcription factor which switches on the genes that code for detoxification enzymes such as superoxide dismutase (SOD), catalyse, and glutathione (Johnson 2007; Eggler&Savinov 2013; Reulandet al. 2013). Furthermore, phytochemicals, particularly members of the thiol class such as sulforaphane, have been shown to exert protective effects by inhibiting the activity of enzymes which convert pro carcinogens to their active, DNA-damaging carcinogen forms (Gasper et al. 2005; Johnson 2007).

Practical evidence of the antioxidant and anticancer properties of phytochemicals has been obtained from a number of laboratory and animal studies involving common carcinogens. One study first demonstrated that chronic exposure to triclocarban in vitro, a chemical commonly found in household detergents, resulted in progressive mutation of noncancerous human breast cells to premalignant cells. The researchers then found that co-exposure of the triclocarban-exposed cells to curcumin significantly reduced the amount and rate of carcinogenesis, as evidenced by decreases in cell proliferation and DNA damage among other endpoints (Sood et al. 2013). In animal studies, rats exposed to cigarette smoke and then given indole-3-carbinol have been found to have a lower lung cancer development rate than those given a standard diet (Morse et al. 1990), while quercetin supplementation of mouse models of benzo(a)pyrene-induced lung cancer has been associated with attenuation of the decreases in antioxidant enzymes, including SOD and catalase, induced by benzo(a)pyrene (Kamaraj et al. 2007). Quercetin anticancer effects exhibited via significant decreases in oxidative stress have also been demonstrated in rat models of N-nitrosodiethylamine-induced liver cancer (Seufi et al. 2009). The antioxidant properties of betalain and other pigments in beetroot have been reported in several animal studies (Reddy et al. 2005; Clifford et al. 2015). Most notably, in one study, rats were randomly allocated to either a normal diet or a diet supplemented with dried beetroot extract. The rats were thenadministered carbon tetrachloride, a well-established carcinogen and reactive oxygen and nitrogen species (RONS) generator. The rats pre-treated with the beetroot were found to express significantly lower levels of lipid peroxidation, a marker of oxidative damage, than those which were not (Vulić et al.2014).

There is also evidence from clinical studies that phytochemicals have antioxidant effects in humans. For example, in one study, volunteers who ate a diet rich in quercetin and kaempferol were found on serum and urine analysis to have higher urinary concentrations of these polyphenols and improved SOD activity (Kim et al. 2003). Eating a meal of onions has been found to increase subjects’ serum levels of quercetin, indicating efficient absorption, and decrease urinary levels of 8-hydroxy-2’-deoxyguanosine, a marker of oxidative stress to DNA, four hours after ingestion of the meal. (Boyle et al. 2000; Wu et al. 2004).Finally, aclinical study carried out in Singapore Chinese reported a significant correlation between increased consumption of cruciferous vegetables, rich in indole-3-carbinol, and decreased urinary levels of metabolites of a tobacco-specific lung carcinogen (Hecht et al. 2004).

Some phytochemicals have anti-inflammatory properties. Although an inflammatory response is an important part of a healthy innate immunity, persistent low-grade increased chronic inflammatory activity is associated with age-related diseases such as Alzheimer’s disease and atherosclerosis. [Lautenbach, Lautenbach, Khansari] Higher levels of inflammatory markers have also been found to be associated with cancer incidence, more advanced cancers at presentation and an increased risk of cancer-specific mortality. [Wolpin, Stark, Ismail]. Markers of chronic inflammation are higher among individuals who are overweight, sedentary, those with poor diets, type II diabetes and the elderly [Hotamisligil, Franceschi]. One reason for this stems from overcompensation of an ailing immune system trying to maintain immunosenescence [Franceschi, Rukavina]. In these groups, poor interleukin (IL)-2 production leads to a decreased cytotoxic capacity of NK and T lymphocytes on a ‘per cell’ basis. To compensate for this, higher levels of inflammatory biomarkers such as C reactive protein, tumour necrosis factor (TNF), IL-6, cytokine antagonists and acute phase proteins are produced which increase concentrations of NK cells and T cells and these transcription factors regulate more than 150 genes involved in mechanisms of cell survival, inflammation, and cancer development. [Hotamisligil, Franceschi, Stark, Ismail].  Numerous phytochemicals have been shown to inhibit NF-kappaB signalling in vitro, particularly the green tea polyphenol epigallocatechin-3-gallate (EGCG), quercetin, curcumin, caffeic acid, and caffeic acid phenethyl ester (Salminen, Carlsen et al. 2010; Reulandet al. 2013). Other anti-inflammatory mechanism of phytochemicals involve the prostaglandin and cox-2 pathways. Chronically increased overproduction of prostaglandins, generated via COX-2, has been implicated in cancer progression, apoptosis, invasion, angiogenesis and metastases [Madaan, Hsu, Liu]. Anti-inflammatory drugs and salicylates found in painkillers and fresh vegetables have been shown to reduce COX-2 activation of prostaglandins which could explain their reported anticancer properties [Beg, Burr]

In vitro laboratory studies have also demonstrated that phytochemicals can modulate cellular and signalling events fundamental to the growth, invasion, and metastasis of cancer cells (Johnson 2007). For example, pomegranate extract, rich in the polyphenol ellagic acid, has been shown to directly inhibit cell growth and induce apoptosis in androgen-sensitive and aggressive human prostate cancer cells (Malik et al. 2005; Rettig et al.2008). Pomegranate juice and its phytochemical components have also been reported to inhibit processes underlying cancer metastasis in a study involving breast cancer cell lines. Pomegranate juice inhibited growth of the breast cancer cells, increased cancer cell adhesion, and decreased cancer cell migration, but did not affect normal cells (Rocha et al. 2012). Furthermore, pomegranate juice was found to inhibit chemotaxis, the process by which breast cancer cells are attracted to a chemokine factor in the bone (Rocha et al. 2012). Curcumin has been found to slow cancer cell growth through several mechanisms, including blocking the cell cycle, increasing the rate of apoptosis, and preventing the invasion and migration of cancer cells (Doraiet al. 2000; Somasundaramet al. 2002; Iqbal et al. 2003; Zhang et al. 2007; Chiu & Su 2009; Park et al. 2013). Curcumin has also been found to halt the growth of stem cells that give rise to breast cancer, without causing toxicity to differentiated cells (Kakaralaet al. 2010). Curcumin has been shown to modulate miRNA expression in cancer, leading to a reduced expression of the anti-apoptotic Bcl-2 protein in breast cancer cells (Yang et al. 2010), and stabilisation of a tumour suppressor gene in colorectal cancer cell lines (Mudduluruet al. 2011). Green tea, rich in EGCG, has been found to impede processes that promote cancer cell proliferation by inhibiting DNA synthesis, cellular de-differentiation, and angiogenesis (Yang et al. 2002; Albrecht et al. 2008; Shanafelt et al. 2009;Braicuet al. 2013; Min & Kwon 2014; Yang et al. 2016). EGCG has also been shown to block ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis (Bachrach& Wang 2002; Wang &Bachrach 2002). Resveratrol has demonstrated epigenetic regulatory properties which influence cell proliferation, survival, and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factors (Park et al. 2015).Caffeic acid phenethyl ester, besides inhibiting NF-kappaBsignalling,has also been shown to inhibit cell motility in vitro and inhibit metastasis of tumor models in vivo (Liao et al. 2003; Butterfield & Keller 2012). Luteolin has been shown in in vitro studies to inhibit tumor growth and metastasis, as well as the epithelial-mesenchymal transition (EMT), a basic biological process underlying cancer initiation and development (Lin et al. 2011; Ruanet al. 2012).

The phytoestrogenic polyphenols have hormonal properties that potentially influence cancers expressing oestrogen or androgen receptors. Most notably, the isoflavones and lignans found in soy products, legumes, and some cruciferous vegetables can weakly bind to the oestrogen receptor without stimulating proliferation of the receptor-bearing cells, thus blocking the binding of more harmful oestrogens, including those produced endogenously, to these receptors (Oseniet al. 2008). This may be the mechanism that at least partially underlies the results of clinical studies such as the previously mentioned Shanghai Breast Cancer Survival Study, in which women with the highest intake of isoflavone and flavanone-rich foods had the greatest overall survival (Boyapatiet al. 2005). In men, phytoestrogenic compounds have been shown to affect 5alpha-reductase and lower endogenous testosterone levels (Evans et al. 1995). This mechanism partially explains why men who regularly eat soy, particularly non-fermented products such as tofu, have a lower risk of prostate cancer (Hwang et al. 2009).

Polyphenols can alsoexert indirect influences on cancer development and progression by supporting or affecting other physical and mental functions. For example, a well-conducted RCT of 56 individuals with major depressive disorder reported that regular intake of curcumin (500 mg twice daily) was significantly more effective than placebo in improving depression-related symptoms after 4 weeks of treatment(Loprestiet al. 2014). This result is important as depression after cancer treatments has been linked to reduced overall survival (Kadan-Lotticket al. 2005; Prasad et al. 2014). Increased dietary polyphenol intake has also been associated with improvements in fatigue (Barton et al. 2013), urinary infections (Bonetta & Di Pierro 2012), and arthralgia (Wang et al. 2007), all of which are adverse effects that often reduce patients’ motivation and ability to be physically active after cancer treatments. Polyphenols thus not only exert beneficial effects in directly reducing these adverse effects, but also improve patients’ ability to exercise more and reap the benefits of regular physical activity, such as reduced cancer relapse or recurrence rates and better quality of life (Davies et al. 2011; Thomas et al. 2016).

An increasing body of evidence is demonstrating important advantages of dietary polyphenols for preventing and mitigating the adverse consequences of T2DM, which include cardiovascular disease and cancer (Knekt et al. 2002; Song et al. 2005; Wedick et al. 2012). A large prospective study of 1,111 T2DM case-control pairs selected from the Nurses’ Health Study (NHS) and the Nurses’ Health Study (NHS) II investigated the urinary excretion of eight polyphenol metabolites, and found that high intake of flavanones and flavonols, as well as the phenolic acid caffeic acid, was linked to a lower incidence of T2DM (Sun et al. 2015). A study of 12,611 incident cases of T2DM across the NHS, NHS II, and Health Professionals Follow-Up Study found that a higher consumption of anthocyanins and anthocyanin-rich fruit was associated with a lower risk of T2DM (Wedicket al. 2012). Furthermore, two clinical studies have reported that the consumption of at least one apple a day, a dietary source rich in flavonoids, was associated with a lower risk of developing T2DM (Knekt et al. 2002; Song et al. 2005). Finally, one prospective study has reported that the intake of polyphenols, especially the large polymeric type of condensed tannins found in legumes, was negatively correlated with the glycaemic index in both normal and diabetic participants, with the polyphenols appearing to be at least partly responsible for the reduced glycaemic response to simultaneously ingested carbohydrate foods (Thompson et al. 1984).

The anti diabetic effects of polyphenols may in part be related to the effects of the pulp and fibre often present in polyphenol-rich foods on slowing gastric emptying (Song et al. 2005; Giovannucci et al. 2010; Wedicket al. 2012; Sun et al. 2015; Turco et al. 2016; Bi et al. 2017). In addition, one laboratory study reported that glucose transport in gut cells was directly inhibitedby flavonoid glycosides and non-glycosylated polyphenols such as EGCG (Johnston et al. 2005). Other in vitro and animal studies have reported that polyphenols may exert their anti diabetic effects through mechanisms including inhibition ofthe production of α-amylase and α-glucosidase, reduction of hepatic glucose output, stimulation of insulin secretion and enhancement of insulin-dependent glucose uptake, and activation of 5′ adenosine mono phosphate-activated protein kinase (AMPK) (Kim et al. 2016).

Type 2 diabetic patients have higher serum insulin levels than non-diabetics, as the pancreas produces more insulin to try to overcome the cellular insulin resistance that characterises T2DM. Hyperinsulinaemia isan independent risk factor for cancer development, related to increased insulin receptor stimulation on cancer cells (Nicolucci 2010).In addition, hyper glycaemia-related oxidative stress and low-grade chronic inflammation, both associated with diabetes, promote malignant transformation (Lorenziet al. 1986; Richardson & Pollack 2005). It is not surprising, therefore, that several studies, including a large cohort study involving over one million people in Australia, have established significant links between T2DMand cancer incidence or mortality, including cancers of the colon, pancreas liver, uterus, kidney, thyroid, gallbladder, and leukaemias (Vigneriet al. 2009; Harding et al. 2016). Likewise, in the UK, a study of 62,809 patients with diabetes found them to have higher risks of colon and pancreatic cancer compared to a similar population without diabetes, especially if the diabetic patients were also obese (Currie et al. 2009). Based on these data and findings, the American Diabetes Association and the American Cancer Society have issued a consensus report stating that T2DMconfers a two-fold higher risk for cancers of the liver, pancreas, and endometrium, and a 1.5-fold higher risk for cancers of the colon and rectum, breast, and bladder (Giovannucciet al. 2010).

Increasing Dietary Phytochemicals?

A qualified nutritionist or dietitian can advise on how to add more phytochemicals to every meal within a sustainable diet plan,tailored to the individual’s needs and tastes, using herbs, spices, teas, vegetables, and fruits. In addition, numerous cooking tips and recipes are now readily available onlinefrom reliable sources, such as the Penny Brohn UK website (www.pennybrohn.org.uk/), a charity supporting those affected by cancer in living well,and the Cancernetblog, which provides regularmeal options, including the ingredients involved, the rationale for their health benefits, and videos showing how they are prepared and cooked (Cancernet UK 2017).

There are several methods for increasing dietary phytochemical intake. Juicing and smoothies in moderation are helpful, but consumption of the whole fruit or vegetable is preferable, as methods which removethe bulk will increase the glycaemic index and free sugar content. Concentrating phytochemical-rich whole foods into a capsule or pill is a convenient way to supplement individuals with poor diets, or to further enhance the nutritional benefits in those whosediets are already adequate. It is certainly easier to conduct prospective interventional studies with supplements, as the quantity and quality of specifical substances can be controlled more precisely. This allows studies to allocate participants to arms involving increased intake of phytochemicals above the dietary average in order to test the hypothesis that phytochemical-rich foods have anticancer effects, and that increasing their intake may thus enhance their benefits. Many people living with and beyond cancer (PLWBC) are certainly attracted to the potential health benefits of food supplements,as over 60% report regular intake (Uzzo et al. 2004; Bauer et al. 2012).

Whole food supplements must be segregated from supplements which containextracted minerals and vitamins, as the overall evidence for the beneficial effects of the latter for individuals with relatively normal nutritional status is not encouraging. Whole food supplements are made from concentrated whole foods, and thus contain the natural combination of nutrients and other components present in the original whole food, in contrast to mineral, vitamin, or other extracted nutrient supplements which contain only those extracted nutrients. However, some specific extracted mineral and vitamin supplements have shown benefits in various clinical studies. For example, a recent meta-analysis reported that women who took vitamin C supplements or increased their dietary intake of vitamin C by >100 mg/day after their breast cancer diagnoses had significantly reduced risks of both breast cancer-specific and total mortality (Harris et al. 2014). An RCT conducted in France studying a daily capsule supplement of a combination of ascorbic acid (120 mg), vitamin E (30 mg), beta-carotene (6 mg),selenium (100 μg), and zinc (20 mg) found no significant reduction in all-cause mortality or total cancer incidence compared to placebo at 7.5 years of follow-up. However, sex-stratified analysis revealed significant reductions in these clinical endpoints in men, but not in women, and further subgroup analyses in men found a reduction in the risk of prostate cancer with supplementation (Hercberg et al. 2004; Meyer et al. 2005). In another interventional trial, four different combinations of daily mineral and vitamin supplements at doses ranging from one to two times the US Recommended Daily Allowances were administered to 29,584 adults in Linxian, China, at a time when its population was known to have widespread micronutrient deficiencies. The study found a reduced risk of gastro esophageal cancer after 5 years of supplementation for the group receiving supplementation with beta-carotene, vitamin E, and selenium, compared to those receiving the other combinations of nutrients (Blot et al. 1993).

Most other clinical studies of supplements of vitamins, minerals,and extracted nutrients, however, have not shown beneficial effects before or after cancer diagnosis, and some report associations with increased risks of cancer. For example, the Beta-Carotene and Retinol Efficacy Trial (CARET) found that daily supplementation of a combination of beta-carotene (30 mg) and vitamin A (25,000 IU retinyl palmitate) was associated with an increased risk of lung cancer compared to placebo (Omenn et al. 1996). The Health Professionals Follow-Up Study (HPFS), which followed the lifestyle habits of 51,529 male professionals for more than 15 years, found that men who took very high doses of supplemental zinc (>100mg/day), or took it for long durations (≥10 years), were more than twice as likely to develop advanced prostate cancer than men who did not take zinc supplements (Leitzmann et al. 2003). A subsequent prospective study followed up the 4,459 men initially diagnosed with prostate cancer in the HPFS, and found that selenium supplementation of ≥140 μg/day after diagnosis was associated with a 2.6-fold greater risk of prostate cancer mortality compared with non-users of supplements (Kenfieldet al. 2015). The Selenium and Vitamin E Cancer Prevention Trial (SELECT) randomised 43,887 men to one of four groups, selenium supplementation alone (200 μg/day), vitamin E supplementation alone (400 IU/day of either rac-alpha-tocopheryl acetate, a supplementation containing both, or placebo and demonstrated a significantly increased risk of prostate cancer with vitamin E supplementation compared with the other three groups after at least 7 years of follow-up (Klein et al. 2011). The negative effect of beta-carotene supplements seen in the CARET study was also found in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, where 20 mg/day of beta-carotene for 5-8 years was associated with an increased risk of lung cancer (Albanes et al. 1996). Interestingly, a subsequent analysis of the results of the ATBC Study showed that men with low pre-supplementation serum levels of beta-carotene had a lower prostate cancer risk following supplementation, while those with high pre-supplementation serum levels of beta-carotene had a higher risk of prostate cancer following supplementation, particularly in smokers (Heinonenet al. 1998).This U-shaped distribution of risk associated with low and high levels of a specific nutrient this also been observed in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study, where those with folate-deficient diets and those with the highest intake of folate both had a higher risk of pancreatic cancer (Chuang et al. 2011). These findings from numerous RCTs have prompted organisations such as the National Cancer Institute to issue statements stating that long-term vitamin and mineral supplements should ideally only be taken to correct a known deficiency (Greenwald et al. 2002).

Studies which have evaluated the cancer risk-reducing effects of supplementation of extracted individual polyphenols have also not produced encouraging results. For example, findings of the benefits of lycopene or genistein taken alone for reducing prostate cancer risk in earlier reports have not been confirmed or replicated in subsequent studies (Giovannucci et al. 2002; Spentzos et al. 2003; Barber et al. 2006; Clark et al. 2006; Brasky et al. 2011). Neither has regular intake of such individual polyphenols been associated with reduction in the risk of breast cancer (Arts & Hollman 2005; Hu et al. 2012). Of more concern are the results ofan RCT from the Memorial Sloan-Kettering Cancer Center, which explored the effects of high-dose genistein supplementation (25.8 g soy protein powder twice daily) for 30 days, or until surgery, in women with early-stage breast cancer. The high-dose genistein supplementation was found to induce changes in the expression of 21 genes, leading to a possibly adverse genetic expression profile in breast cancer. Furthermore, the addition of blood serum obtained from women in the supplementation group to laboratory tumor cells caused the tumor cells to proliferate faster and over express the tumourigenic growth factor receptor FGFR2 (Shikeet al. 2014). Based on this evidence, concentrating phytoestrogens into strong supplements is not currently recommended.

More recently, academic attention has turned towards the evaluation of dried and concentrated whole foods which contain an array of polyphenols and other phytochemicals. Reassuringly, no notable study of non-phytoestrogenic whole food supplements thus far has shown any detrimental effects on cancer outcomes, and some studies have demonstrated considerable benefits. For example, a randomised phase II dose-exploring study carried out at Johns Hopkins found that men taking either of two doses of a pomegranate extract supplement (1 g or 3 g) for 18 months experienced significant reduction in progression of PSA levels compared to the baseline PSA progression rate pre-treatment (Paller et al. 2013). A phase II trial of a green tea concentrate supplement containing a standardised dose of EGCG (2000 mg per dose), administered twice daily to chronic lymphocytic leukemia patients for up to 6 months, found that the treatment was associated with a sustained and clinically significant decrease in the absolute lymphocyte count in 30% of patients (Shanafelt et al. 2013). A small study of men with prostate cancer scheduled for radical prostatectomy reported that daily administration of a green tea concentrate supplement containing 800 mg of EGCG (and a total of 1300mg of tea polyphenols) for several weeks, from initiation of the study until the scheduled prostatectomy, caused a significant reduction in the serum levels of PSA and several cancer-promoting growth factors compared to pre-study baseline levels (McLarty et al. 2009). In the large Vitamins and Lifestyle (VITAL) cohort study, intake of grape seed extract supplements was shown to be associated with a significantly reduced total risk of prostate cancer after 6 years of follow-up (Braskyet al.2011). Another small crossover RCT  found that a dietary supplement containing isoflavone-rich foods, including 62.5 mg of soy and 15 mg of lycopene among other phytochemicals and antioxidants, administered 4 times a day for treatment periods lasting 10 weeks, significantly delayed PSA progression compared to placebo in men with a history of prostate cancer who had received potentially curative therapies (Schröder et al. 2005). Interestingly, one of the most popular supplements, saw palmetto fruit extract, despite demonstrating beneficial effects in early small studies, has shown no benefits for improving the symptoms of benign prostatic hyperplasia, delaying PSA progression, or reducing prostate cancer risks larger observational or randomised interventional evaluations of its effects (Bent et al. 2006; Bonnar-Pizzorno et al. 2006; Barry et al. 2011; Andrioleet al.2013).

To date, the largest RCT analyzing the effects of phytochemical-rich whole food extract son cancer risk has been the UK National Cancer Research Network  Study (Thomas et al. 2014). This study combined four different dried foods (pomegranate, green tea, broccoli and turmeric) into a single tablet, taken 3 times a day, in order to provide a wide spectrum of synergistically-acting nutrients whilst avoiding over-consumption of any particular phytochemical. The trial involved 200 men with localised prostate cancer, managed with either active surveillance or watchful waiting. The results showed a statistically significant 63% reduction in median PSA progression rate at 6 months of intervention for the group randomised to the supplement compared to placebo. A further analysis of the men’s MRI scans demonstrated that presence of disease, cancer size, and growth pattern son the scans correlated with PSA changes, providing support for the conclusion that the supplement was exerting beneficial effects not just on PSA levels, but on the disease itself (Thomas et al. 2014; Thomas et al. 2015). Furthermore, the supplement was well-tolerated, and there was no effect on testosterone levels. At the end of the study, significantly more men opted to remain on surveillance and continue with lifestyle and nutritional interventions, such as taking the food supplement, rather than proceed to expensive radiotherapy, surgery, or medical castration options, which can cause unpleasant adverse effects such as depression, hot flushes, weight gain, osteoporosis, and erectile dysfunction (Thomas et al. 2014).

Polyphenols and Chemotherapy

There have been some concerns that polyphenols may interfere with oncology treatments, especially considering their antioxidant properties. The section above has highlighted that antioxidant properties are only one of the many mechanisms of action exerted by polyphenols. Moreover, polyphenols mainly enhance the production and action of antioxidant enzymes, rather than having a direct effect on free radical absorption, unlike other nutrients such as vitamins A and E (Scalbert et al. 2005; Lüet al. 2010; Reuland et al. 2013).Most importantly, laboratory studies have reported that polyphenols exert direct anticancer properties by helping to reduce excessive cell proliferation, de-differentiation, loss of cell adhesion, and metastasis, and supporting apoptosis (Dorai et al. 2000; Somasundaram et al. 2002; Yang et al. 2002; Iqbal et al. 2003; Malik et al. 2005; Handler et al. 2007; Johnson 2007; Zhang et al. 2007; Shanafelt et al. 2009; Mudduluru et al. 2011; Butterfield & Keller 2012; Park et al. 2015). It is not surprising, then, that several studies have actually found that polyphenols enhance the cytotoxic effects of chemotherapy, rather than impede it. For example, a two-fold greater anticancer efficacy of intravenous curcumin and docetaxol, a chemotherapy drug, compared with docetaxol alone, was reported in a transplanted xenograft mouse model of lung cancer, without an increase in damage to normal tissue (Yin et al. 2012). Curcumin has also been found to enhance the effectiveness of cisplatin, another chemotherapy drug, by helping to reduce cell proliferation in a study of laryngeal carcinoma cancer stem cell model (Zhang et al. 2013). Another in vitro study reported that beetroot juice both promoted apoptosis of breast cancer cells after exposure of the cells to the cytotoxic chemotherapy agent doxorubicin, and protected normal cardiomyocytes, or heart muscle cells, from the toxic effects of doxorubicin (Das et al. 2013).

These findings from laboratory studies are encouraging, but the true clinical potential of polyphenols and other phytochemicals in cancer can only be tested within large RCTs. Fortunately, there are currently over ten on- going studies registered with the National Institute of Health, US, and a number of studies are also ongoing in the UK. Notably, the Arthro-T RCT (Eudra CT number 2017-000201-20) is investigating whether a supplement made from a blend of polyphenol-rich foods could help to reduce joint pains and fatigue related to cancer treatments, and thus allow patients to achieve greater levels of physical activity.

Emerging evidence suggests some plant extracts may also have a role in preventing cutaneous toxicities of cancer treatments. Distressing nail damage (onycholysis) is common amongst patients receiving chemotherapy, especially taxanes, causing pain, disfigurement secondary infection and interference with activities of daily living (Minisini et al 2003). One recent RCT (the UK polybalm study) explored the bioactive properties of a number African herbs including leleshwa, gaultheria procumbens, lavandulaofficinalis, eucalyptus globulus and tarchonanthuscamphoratus. The phenolics and other phytochemical in these herbs have been reported to have moisturising, anti-inflammatory, anti-microbial and anti-oxidant properties (Delaquis P et al 2002, Smith-Palmer A et al, 2002, Baratta et al 2001). The participants on chemotherapy randomised to the investigational balm had little of no nail damage or discomfort compared to over 50% in the placebo group recorded with four different measures of toxicity and this difference was highly statistically significant (Thomas et al 2017). It was correctly hypothesized, by the researchers, that the oils in the polybalm were sufficiently absorbed into the nail bed to prevent cracking and splitting, act as a local antidote to the chemotherapy, protecting the proliferating stem cells. In addition their anti-microbial properties helped prevent secondary infection so overall keep the nail healthy and intact. The success of this trial opens up possibilities for topical preventative interventions for other skin conditions such as hand foot syndrome, hair loss and even within mouth washes.

Conclusion

There is increasingly convincing evidence to show that plant phytochemicals have significant health benefits for humans. Regular phytochemical in take is linked to a reduce risk of developing cancer and benefit patients living with and beyond cancer diagnosis and treatment. “Living Well” programmes are being introduced in the UK, largely driven by the National Cancer Survivorship Initiative and guidelines from influential organisations, and are beginning to highlight the importance of a regular intake of colourful variety of vegetables, fruits, legumes, nuts, herbs and spices to harness the beneficial effects of the numerous phytochemicals available through our food alongside other lifestyle factors. Going a step further and concentrating phytochemical-rich foods into nutritional supplements or balms provides an opportunity to boost their beneficial effects. Although some studies of concentrated minerals, vitamins, and phytoestrogenic supplements have reported detrimental effects, there have been no RCTs reporting significant detrimental effects for whole, non-phytoestrogenic food supplements. Some RCT’s have reported significant advantages for these types of supplements in slowing cancer progression and preventing side effects of chemotherapy. Despite these potential benefits and reports that over 60% of cancer survivors take nutritional supplements, many oncologists are reluctant to discuss the pros and cons of taking such supplements with their patients. This reluctance is due in part to the lack of large, well-conducted RCTs exploring phytochemical-rich interventions, with a significant proportion of the evidence for the benefits of phytochemical supplementation arising from observational studies, which makes it difficult to assess causality (Voorripset al. 2000; Liao et al. 2004). Hopefully this trend will change,  with forthcoming evidence from interventional studies being performed around the world.


References

Burr A. Effect of phytochemicals on growth and prostaglandin E2 (PGE2) synthesis in PC-3 cells, a prostate cancer cell line. Published online: proquest.2011.61.html

Beg S, Swain S, Hasan H et al Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives Pharmacogn Rev. 2011; 5(10): 120–137.

Madaan S, Abel PD, Chaudhary KS, et al. Cytoplasmic induction and over-expression of cyclooxygenase-2 in human prostate cancer: implications for prevention and treatment. BJU Int 2000;86:736–41.
107

Hsu AL, Ching TT, Wang DS, et al. The cyclooxygenases-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cellsindependently of Bcl-2. J Biol Chem 2000;275:11397–403.
108 Liu XH, Yao S, Kirschenbaum A, et al. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. Cancer Res 1998;58:4245–9.

Stark JR, Li H, Kraft P, et al. Circulating pre-diagnostic interleukin-6 and C-reactive protein and prostate cancer incidence and mortality. Int J Cancer 2009;124:2683–9.

101 Ismail HA, Lessard L, Mes-Masson AM, et al. Expression of NF-kappaB in prostate cancer lymph node metastases. Prostate 2004;58:308–13.

Michalaki V, Syrigos K, Charles P, et al. Serum levels of IL-6 and TNF-alpha correlate with clinicopathological features and patient survival in patients with prostate cancer. Br J Cancer 2004;90:2312–16.

Franceschi C, Monti D, Sansoni P, et al. The immunology of exceptional individuals: the lesson of centenarians. Immunol Today 1995;16:12–16.

Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444:860–7.

Salminen A, Kauppinen A, Kaarniranta K. Phytochemicals suppress nuclear factor-κB signaling: impact on health span and the aging process.Curr Opin Clin Nutr Metab Care. 2012 ; 15(1):23-8. 

Wolpin BM, Bao Y, Qian ZR. Hyperglycemia, insulin resistance, impaired pancreatic β-Cell function, and risk of pancreatic cancer. Natl Cancer Inst 2013;105:1027–35.

Rukavina D, Laskarin G, Rubesa G, et al. Age-related decline of perforin expression in human cytotoxic T lymphocytes and natural killer cells. Blood 1998;92:2410–20.

Lautenbach A, Breitmeier D, Kuhlmann S, et al. Human obesity reduces the number of hepatic leptin receptor (Ob-R) expressing NK-cells. Endocr Res 2011;36:158–66.

Khansari N, Shakiba Y, Mahmoudi M, et al. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov 2009;3:73–80.

 

  1. AICR (American Institute for Cancer Research) (2017) Phytochemicals: the cancer fighters in the foods we eat. Available at: http://www.aicr.org/reduce-your-cancer-risk/diet/elements_phytochemicals.html (accessed 25 June 2017).
  2. Albanes D, Heinonen OP, Taylor PR et al.(1996) Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. Journal of the National Cancer Institute.88: 1560-70.
  3. Albrecht DS, Clubbs EA, Ferruzzi M et al. (2008) Epigallocatechin-3-gallate (EGCG) inhibits PC-3 prostate cancer cell proliferation via MEK-independent ERK1/2 activation. Chemico-Biological Interactions171: 89-95.
  4. Andriole GL, McCullum-Hill C, Sandhu GS et al. (2013) The effect of increasing doses of saw palmetto fruit extract on serum prostate specific antigen: analysis of the CAMUS randomized trial. Journal of Urology189: 486-92.
  5. Bachrach U & Wang YC (2002) Cancer therapy and prevention by green tea: role of ornithine decarboxylase. Amino Acids 22: 1-13.
  6. Banim PJ, Luben R, McTaggart A et al. (2012) Dietary antioxidants and the aetiology of pancreatic cancer: a cohort study using data from food diaries and biomarkers. Gut62: 1489-96.
  7. Barber NJ, Zhang X, Zhu G et al. (2006) Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer and Prostatic Diseases9: 407-13.
  8. Barry MJ, Meleth S, Lee JY et al. (2011) Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. Journal of the American Medical Association306: 1344-51.
  9. Barton DL, Liu H, Dakhil SR et al. (2013) Wisconsin Ginseng (Panaxquinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial. Journal of the National Cancer Institute105: 1230-8.
  10. Bauer CM, Johnson EK, Beebe-Dimmer JL et al. (2012) Prevalence and correlates of vitamin and supplement usage among men with a family history of prostate cancer. Integrative Cancer Therapies11: 83-9.
  11. Bent S, Kane C, Shinohara K et al. (2006) Saw Palmetto for benign prostatic hyperplasia. New England Journal of Medicine354: 557-66.
  12. Bi X, Lim J, Christiani JH et al. (2017) Spices in the management of diabetes mellitus. Food Chemistry217: 281-93.
  13. Block G, Patterson B & Subar A (1992) Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutrition and Cancer 18: 1–29.
  14. Blot WJ, Li JY, Taylor PR et al. (1993) Nutritional intervention trials in Linxian China: supplementation with specific vitamin/mineral combinations, cancer incidence and disease specific mortality in the general population. Journal of the National Cancer Institute85: 1483-91.
  15. Bonetta A & Di Pierro F (2012) Enteric-coated, highly standardized cranberry extract reduces risk of UTIs and urinary symptoms during radiotherapy for prostate carcinoma. Cancer Management and Research 4: 281-6.
  16. Bonnar-Pizzorno RM, Littman AJ, Kestin M et al. (2006) Saw palmetto supplement use and prostate cancer risk. Nutrition and Cancer55: 21-7.
  17. Boyapati SM, Shu XO &Ruan ZX (2005) Soy food intake and breast cancer survival: a follow up of the Shanghai Breast Cancer Study. Breast Cancer Research and Treatment 92: 11–7.
  18. Boyle SP, Dobson VL, Duthie SJ et al. (2000) Absorption and DNA protective effects of flavonoid glycosides from an onion meal. European Journal of Nutrition39: 213–23.
  19. Bradbury KE, Appleby PN, Key TJ (2014). Fruit andvegetable intake and cancer in the EPIC study. Am J ClinNutr (2014) 100 (1): 394.
  20. Braicu C, Gherman CD, Irimie A et al. (2013) Epigallocatechin-3-gallate (EGCG) inhibits cell proliferation and migratory behaviour of triple negative breast cancer cells. Journal of Nanoscience and Nanotechnology13: 632-7.
  21. Brasky TM, Kristal AR, Navarro SL et al. (2011) Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort. Nutrition and Cancer63: 573-82.
  22. Buck K, Vrieling A, Zaineddin AK et al. (2011) Serum enterolactone and prognosis of post-menopausal breast cancer. Journal of Clinical Oncology29: 3730-8.
  23. Butterfield DA & Keller J (2012) Antioxidants and antioxidant treatment in disease. Biochimica et BiophysicaActa1822: 615.
  24. Cancernet UK (2017) Healthy recipes. Available at: http://blog.cancernet.co.uk/category/healthy-recipes/ (accessed 12 January 2017).
  25. Carlsen MH, Halvorsen BL, Holte K et al. (2010) The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide. Nutrition Journal9:3 doi:10.1186/1475-2891-9-3.
  26. Chiu TL & Su CC (2009) Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. International Journal of Molecular Medicine23: 469-75.
  27. Rowan T. Chlebowski††, Aaron K. Aragaki†, Garnet L. Anderson†, Low-Fat Dietary Pattern and Breast Cancer Mortality in the Women’s Health Initiative Randomized Controlled Trial DOI: 10.1200/JCO.2016.72.0326 Journal of Clinical Oncology – published online before print June 27, 2017
  28. Chuang SC, Stolzenberg-Solomon R, Ueland PM et al. (2011) A U-shaped relationship between plasma folate and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. European Journal of Cancer47: 1808-16.
  29. Clark PE, Hall MC, Borden LS et al. (2006) Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy. Urology67: 1257-61.
  30. Clifford T, Howatson G, West DJ et al. (2015) The potential benefits of red beetroot supplementation in health and disease. Nutrients7: 2801-22.
  31. Currie CJ, Poole CD & Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia52: 1766-77.
  32. Das S, Williams DS, Das A et al. (2013) Beet root juice promotes apoptosis in oncogenic MDA-MB-231 cells while protecting cardiomyocytes under doxorubicin treatment. Journal of Experimental Secondary Science. 2: 1–6.
  33. Davies NJ, Batehup L & Thomas R (2011) The role of diet and physical activity in breast, colorectal, and prostate cancer survivorship: a review of the literature. British Journal of Cancer105(Suppl 1): S52-73.
  34. Delaquis P et al (2002): Antimicrobial activity of essential oils. Int J Food Microbiol 74(1-2):101-9.
  35. Dorai T, Gehani N & Katz A (2000) Therapeutic potential of curcumin in human prostate cancer. II. Curcumin inhibits tyrosine kinase activity of epidermal growth factor receptor and depletes the protein. Molecular Urology4: 1-6.
  36. Eggler AL &Savinov SN (2013) Chemical and biological mechanisms of phytochemical activation of Nrf2 and importance in disease prevention. Recent Advances in Phytochemistry43: 121-55.
  37. Evans BAJ, Griffiths K & Morton MS (1995) Inhibition of 5alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. Journal of Endocrinology147: 295-302.
  38. Gasper AV, Al-Janobi A, Smith JA et al. (2005) Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. American Journal of Clinical Nutrition82: 1283–91.
  39. Giovannucci E, Rimm EB, Liu Y et al. (2002) A prospective study of tomato products, lycopene and prostate cancer risk. Journal of the National Cancer Institute 94: 391-8.
  40. Giovannucci E, Harlan DM, Archer MC et al. (2010) Diabetes and cancer: a consensus report. Diabetes Care33: 1674-85.
  41. Greenwald P, Milner JA, Anderson DE et al. (2002) Micronutrients in cancer chemoprevention. Cancer and Metastasis Review 21: 217-30.
  42. Handler N, Jaeger W, Puschacher H et al. (2007) Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors. Chemical & Pharmaceutical Bulletin55: 64-71.
  43. Harding JL, Shaw JE, Peeters A et al. (2016) Age-specific trends from 2000-2011 in all-cause and cause-specific mortality in type 1 and type 2 diabetes: a cohort study of more than one million people. Diabetes Care39: 1018-26.
  44. Harris HR, Orsini N &Wolk A (2014) Vitamin C and survival among women with breast cancer: a meta-analysis. European Journal of Cancer50: 1223-31.
  45. Hecht SS, Carmella SG, Kenney PM et al. (2004) Effects of cruciferous vegetable consumption on urinary metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in Singapore Chinese. Cancer Epidemiology, Biomarkers & Prevention13: 997-1004.
  46. Heinen MM, Hughes MC, Ibiebele TI et al. (2007) Intake of antioxidant nutrients and the risk of skin cancer. European Journal of Cancer43: 2707-16.
  47. Heinonen OP, Albanes D, Virtamo J et al. (1998) Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. Journal of the National Cancer Institute90: 440-6.
  48. Hercberg S, Galan P, Preziosi P et al. (2004) The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Archives of Internal Medicine164: 2335-42.
  49. Higdon J & Drake VJ (2012) An Evidence-Based Approach to Phytochemicals and Other Dietary Factors, 2ndedn. Thieme Medical Publishers: Stuttgart.
  50. Hu F, Wang YB, Liang J et al. (2012) Carotenoids and breast cancer risk: a meta-analysis and meta-regression. Breast Cancer Research and Treatment131: 239-53.
  51. Hwang YW, Kim SY, Jee SH et al. (2009) Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutrition and Cancer 61: 598-606.
  52. Iqbal M, Sharma SD, Okazaki Y et al. (2003) Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacology & Toxicology92: 33-8.
  53. Johnson IT (2007) Phytochemicals and cancer. Proceedings of the Nutrition Society66: 207-15.
  54. Johnston K, Sharp P, Clifford M et al. (2005) Dietary polyphenols decrease glucose uptake by human intestinal Caco-2 cells. FEBS Letters579: 1653-7.
  55. Joseph MA, Moysich KB, Freudenheim JL et al. (2004) Cruciferous vegetables, genetic polymorphisms and prostate cancer risk. Nutrition and Cancer50: 206-13.
  56. Kadan-Lottick NS, Vanderwerker LC, Block SD et al. (2005) Psychiatric disorders and mental health service use in patients with advanced cancer: a report from the coping with cancer study. Cancer104: 2872-81.
  57. Kakarala M, Brenner DE, Korkaya H et al. (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Research and Treatment122: 777-85.
  58. Kamaraj S, Vinodhkumar R, Anandakumar P et al. (2007) The effects of quercetin on antioxidant status and tumor markers in the lung and serum of mice treated with benzo(a)pyrene. Biological and Pharmaceutical Bulletin30: 2268-73.
  59. Kenfield SA, Van Blarigan EL, DuPre N et al. (2015) Selenium supplementation and prostate cancer mortality. Journal of the National Cancer Institute. doi:10.1093/jnci/dju360.
  60. Key TJ (2011) Fruit and vegetables and cancer risk. British Journal of Cancer104: 6–11.
  61. Kim HY, Kim OH & Sung MK (2003) Effects of phenol-depleted and phenol-rich diets on blood markers of oxidative stress, and urinary excretion of quercetin and kaempferol in healthy volunteers. Journal of the American College of Nutrition 22: 217-23.
  62. Kim Y, Keogh JB & Clifton PM (2016) Polyphenols and glycemic control. Nutrients. doi:10.3390/nu8010017.
  63. Klein EA, Thompson IM, Tangen CM et al. (2011) Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Journal of the American Medical Association306: 1549-56.
  64. Knekt P, Jarvinen R, Seppanen R et al. (1997) Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. American Journal of Epidemiology146: 223–30.
  65. Knekt P, Kumpulainen J, Järvinen R et al. (2002) Flavonoid intake and risk of chronic diseases. American Journal of Clinical Nutrition 76: 560–8.
  66. Le Marchand L, Murphy SP, Hankin JH et al. (2000) Intake of flavonoids and lung cancer. Journal of the National Cancer Institute92: 154 –60.
  67. Lee SJ & Wong M (2014) Nano- and microencapsulation of phytochemicals. In: Nano- and Microencapsulation for Foods (edKwak HS), 1stedn. John Wiley and Sons Ltd: Chichester.
  68. Leitzmann MF, Stampfer MJ, Wu K et al. (2003) Zinc supplement use and risk of prostate cancer. Journal of the National Cancer Institute95: 1004-7.
  69. Li C, Ford ES, Zhao G et al. (2011) Serum alpha-carotene concentrations and risk of death among US adults: The Third National Health and Nutrition Examination Survey Follow-up Study. Archives of Internal Medicine171: 507-15.
  70. Liao HF, Chen YY, Liu JJ et al. (2003) Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumor invasion, and metastasis. Journal of Agricultural and Food Chemistry51: 7907-12.
  71. Liao J, Yang GY, Park ES et al. (2004) Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in A/J mice by oral administration of green tea. Nutrition and Cancer48: 44-53.
  72. Lin YS, Tsai PH, Kandaswami CC et al. (2011) Effects of dietary flavonoids, luteolin, and quercetin on the reversal of epithelial-mesenchymal transition in A431 epidermal cancer cells. Cancer Science102: 1829-39.
  73. Loftfield E, Freedman ND, Graubard BI et al. (2015) Coffee drinking and cutaneous melanoma risk in the NIH-AARP Diet and Health Study. Journal of the National Cancer Institute107: 1-9.
  74. Lopresti AL, Maes M, Maker GL et al. (2014) Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. Journal of Affective Disorders167: 368-75.
  75. Lorenzi M, Montisano DF, Toledo S et al. (1986) High glucose induces DNA damage in cultured human endothelial cells. Journal of Clinical Investigation77: 322-5.
  76. Lü JM, Lin PH, Yao Q et al. (2010) Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. Journal of Cellular and Molecular Medicine14: 840-60.
  77. Malik A, Afaq F, Sarfaraz S et al. (2005) Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proceedings of the National Academy of Sciences102: 14813–8.
  78. Martin C, Zhang Y, Tonelli C et al. (2013) Plants, diet, and health. Annual Review of Plant Biology64: 19-46.
  79. McLarty J, Bigelow RL, Smith M et al. (2009) Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prevention Research 2: 673-82.
  80. Meyer F, Galan P, Douville P et al. (2005) Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial. International Journal of Cancer116: 182-6.
  81. Min KJ & Kwon TK (2014) Anticancer effects and molecular mechanisms of epigallocatechin-3-gallate. Integrative Medicine Research3: 16-24.
  82. Minisini AM, Tosti A, SobreroAF et al (2003): Taxane-induced nail changes. Ann Oncol 14:333-337.
  83. Morse MA, LaGreca SD, Amin SG et al. (1990) Effects of indole-3-carbinol on lung tumorigenesis and DNA methylation induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and on the metabolism and disposition of NNK in A/J mice. Cancer Research50: 2613-7.
  84. Mudduluru G, George-William JN, Muppala S et al. (2011) Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Bioscience Reports31: 185-97.
  85. Nicolucci A (2010) Epidemiological aspects of neoplasms in diabetes. ActaDiabetologica47: 87–95.
  86. Ogunleye AA, Xue F &Michels KB (2010) Green tea and breast cancer risk or recurrence: a meta-analysis. Breast Cancer Research and Treatment119: 477-84.
  87. Omenn GS, Goodman GE, Thornquist MD et al. (1996) Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. Journal of the National Cancer Institute88: 1550-9.
  88. Ornish D, Weidner G, Fair WR et al. (2005) Intensive lifestyle changes may affect the progression of prostate cancer. Journal of Urology174: 1065-9.
  89. Oseni T, Patel R, Pyle J et al. (2008) Selective estrogen receptor modulators and phytoestrogens. Planta Medica74: 1656-65.
  90. Paller CJ, Ye X, Wozniak PJ et al. (2013) A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer and Prostatic Diseases16: 50-5.
  91. Pantuck AJ, Leppert JT, Zomorodian N et al. (2006) Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clinical Cancer Research12: 4018-26.
  92. Park SY, Murphy SP, Wilkens LR et al. (2008) Legume and isoflavone intake and prostate cancer risk: The Multiethnic Cohort Study. International Journal of Cancer. 123: 927-32.
  93. Park W, Ruhul Amin ARM, Chen ZG et al. (2013) New perspectives of curcumin in cancer prevention. 6: 387-400.
  94. Park EJ, John M &Pezzuto JM (2015) The pharmacology of resveratrol in animals and humans. Biochimica et BiophysicaActa (BBA) – Molecular Basis of Disease1852: 1071-113
  95. Pierce JP, Natarajan L, Caan BJ et al. (2007a) Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women’s Healthy Eating and Living (WHEL) randomized trial. Journal of the American Medical Association298: 289-98.
  96. Pierce JP, Stefanick ML, Flatt SW et al. (2007b) Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. Journal of Clinical Oncology25: 2345-51.
  97. Prasad SM, Eggener SE, Lipsitz SR et al. (2014) Effect of depression on diagnosis, treatment, and mortality of men with clinically localized prostate cancer.Journal of Clinical Oncology 32: 2471-8.
  98. Reddy MK, Alexander-Lindo RL & Nair MG (2005) Relative inhibition of lipid peroxidation, cyclooxygenase enzymes, and human tumor cell proliferation by natural food colors. Journal of Agricultural and Food Chemistry53: 9268-73.
  99. Rettig MB, Heber D, An J et al. (2008) Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-kappa B-dependent mechanism. Molecular Cancer Therapeutics 7: 2662-71.
  100. Reuland DJ, Khademi S, Castle CJ et al. (2013) Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress. Free Radical Biology and Medicine56: 102–11.
  101. Richardson LC & Pollack LA (2005) Therapy insight: influence of type 2 diabetes on the development and outcomes of cancer. Nature Clinical Practice Oncology2: 48-53.
  102. Rocha A, Wang L, Penichet M et al. (2012) Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer. Breast Cancer Research and Treatment136: 647-58.
  103. Rodríguez-Ramiro D, Ramos S, López-Oliva E et al. (2011) Cocoa-rich diet prevents azoxymethane-induced colonic preneoplastic lesions in rats by restraining oxidative stress, cell proliferation and inducing apoptosis. Molecular Nutrition & Food Research55: 1895-9.
  104. Ruan JS, Liu YP, Zhang L et al. (2012) Luteolin reduces the invasive potential of malignant melanoma cells by targeting beta3 integrin and the epithelial-mesenchymal transition. ActaPharmacologicaSinica33: 1325-31.
  105. Scalbert A, Johnson IT & Saltmarsh M (2005) Polyphenols: antioxidants and beyond. American Journal of Clinical Nutrition81(suppl): 215S-7S.
  106. Schröder FH, Roobol MJ, Boevé ER et al. (2005) Randomized, double-blind, placebo-controlled crossover study in men with prostate cancer and rising PSA: effectiveness of a dietary supplement. European Urology48: 922-30.
  107. Seufi AM, Ibrahim SS, Elmaghraby TK et al. (2009) Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences. Journal of Experimental and Clinical Cancer Research. doi:10.1186/1756-9966-28-80.
  108. Shanafelt TD, Call TG, Zent CS et al. (2009) Phase I trial of daily oral polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphatic leukemia. Journal of Clinical Oncology27: 3808–14.
  109. Shanafelt TD, Call TG, Zent CS et al. (2013) Phase 2 trial of daily, oral polyphenon E in patients with asymptomatic, Rai stage 0-II chronic lymphocytic leukemia (CLL). Cancer119: 363-70.
  110. Shike M, Doane AS, Russo L et al. (2014) The effects of soy supplementation on gene expression in breast cancer: a randomized placebo-controlled study. Journal of the National Cancer Institute. doi:10.1093/jnci/dju189.
  111. Shu XO, Zheng Y, Cai H et al. (2009) Soy food intake and breast cancer survival. Journal of the American Medical Association302: 2437-43.
  112. Somasundaram S, Edmund NA, Moore DT et al. (2002) Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Research62: 3868-75.
  113. Smith-Palmer A, Stuart J, Fyfe L (2002): Antimicrobial plant essential oils. Applied Microbiol26 (2):118-22.

  1. Song Y, Manson J, Buring J et al. (2005) Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis. Journal of the American College of Nutrition24: 376–84.
  2. Song F, Qureshi A & Han J (2012) Increased caffeine intake is associated with reduced risk of basal cell carcinoma of the skin. Cancer Research72: 3282-9.
  3. Sood S, Choudhary S & Wang HC (2013) Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin. Biochemical and Biophysical Research Communications438: 600-6.
  4. Spentzos D, Mantzoros C, Regan MM et al. (2003) Minimal effect of a low-fat/high soy diet for asymptomatic, hormonally naïve prostate cancer patients. Clinical Cancer Research9: 3282-7.
  5. Sun CL, Yuan JM, Koh WP et al. (2007) Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study. Carcinogenesis28: 2143-8.
  6. Sun Q, Wedick NM, Tworoger SS et al. (2015) Urinary excretion of select dietary polyphenol metabolites is associated with a lower risk of type 2 diabetes in proximate but not remote follow-up in a prospective investigation in 2 cohorts of US women. Journal of Nutrition145: 1280-8.
  7. Swann R, Perkins KA, Velentzis LS et al. (2013) The DietCompLf study: A prospective cohort study of breast cancer survival and phytoestrogen consumption. Maturitas75: 232-40.
  8. Thomas R, Williams M, Sharma H et al. (2014) A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer: the UK National Cancer Research Network (NCRN) Pomi-T study. Prostate Cancer and Prostatic Diseases17: 180–6.
  9. Thomas R, Shaikh M, Cauchi M et al. (2015) Prostate cancer progression defined by MRI correlates with serum PSA in men undergoing lifestyle and nutritional interventions for low risk disease. Journal of Lifestyle Diseases and Management1: 1-8.
  10. Thomas RJ, Kenfield SA & Jimenez A (2016) Exercise-induced biochemical changes and their potential influence on cancer: a scientific review. British Journal of Sports Medicine.doi:10.1136/bjsports-2016-096343.
  11. Thomas R, Butler E, MacchiF and Williams M. Phytochemicals in cancer prevention and management? British Journal of Cancer Management 2015 Volume 8 (2), pp 34-9.
  12. Thomas R, Berkovitz S, Smith S et al (2017). A double blind, randomised controlled trial of a polyphenol rich nail balm to prevent chemotherapy-induced onycholysis – The UK PolyBalm Study American Society of Clinical Oncology Conference abstracts Journal of Clinical Oncology 10103.
  13. Thompson LU, Yoon JH, Jenkins DJ et al. (1984) Relationship between polyphenol intake and blood glucose response of normal and diabetic individuals.American Journal of Clinical Nutrition39: 745-51.
  14. Tung KH, Wilkens LR, Wu AH et al. (2005) Association of dietary vitamin A, carotenoids, and other antioxidants with the risk of ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention14: 669-76.
  15. Turco I, Bacchetti T, Bender C et al. (2016) Polyphenol content and glycemic load of pasta enriched with Faba bean flour. Functional Foods in Health & Disease6: 291-305.
  16. Uzzo RG, Brown JG, Horwitz EM et al. (2004) Prevalence and patterns of self-initiated nutritional supplementation in men at high risk of prostate cancer. BJU International93: 955-60.
  17. van Die MD, Bone KM, Williams SG et al. (2014) Soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials. BJU International113: E119-30.
  18. Vigneri P, Frasca F, Sciacca L et al. (2009) Diabetes and cancer. Endocrine-Related Cancer16: 1103-23.
  19. Voorrips LE, Goldbohm RA, van Poppel G et al. (2000) Vegetable and fruit consumption and risks of colon and rectal cancer in a prospective cohort study: the Netherlands Cohort Study on Diet and Cancer. American Journal of Epidemiology152: 1081-92.
  20. Vulić JJ,Ćebović TN, Čanadanović-Brunet, JM et al. (2014) In vivo and in vitro antioxidant effects of beetroot pomace extracts. Journal of Functional Foods 6: 168–75.
  21. Wang YC &Bachrach U (2002) The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG). Amino Acids22: 131-43.
  22. Wang Y, Hodge AM, Wluka AE et al. (2007) Effect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects: a cross-sectional study. Arthritis Research & Therapy9: R66.
  23. WCRF/AICR (World Cancer Research Fund/American Institute for Cancer Research) (2007) Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. AICR: Washington DC.
  24. Wedick NM, Pan A, Cassidy A et al. (2012) Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. American Journal of Clinical Nutrition95: 925-33.
  25. Wu LL, Chiou CC, Chang PY et al. (2004) Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. ClinicaChimicaActa339: 1-9.
  26. Yan L &Spitznagel EL (2009) Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis. American Journal of Clinical Nutrition89: 1155-63.
  27. Yang CS, Maliakal P &Meng X (2002) Inhibition of carcinogenesis by tea. Annual Review of Pharmacologyand Toxicology42: 25-54.
  28. Yang J, Cao Y, Sun J et al. (2010) Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells. Medical Oncology27: 1114-8.
  29. Yang C, Du W & Yang D (2016) Inhibition of green tea polyphenol EGCG((-)-epigallocatechin-3-gallate) on the proliferation of gastric cancer cells by suppressing canonical wnt/beta-catenin signalling pathway. International Journal of Food Sciences and Nutrition67: 818-27.
  30. Yin H, Guo R, Zheng Y et al. (2012) Synergistic antitumor efficiency of docetaxel and curcumin against lung cancer. ActaBiochimica et BiophysicaSinica44: 147-53.
  31. Zhang HN, Yu CX, Zhang PJ et al. (2007) Curcumin downregulates homeobox gene NKX3.1 in prostate cancer cell LNCaP. ActaPharmacologicaSinica28: 423-30.
  32. Zhang H, Yu T, Wen L et al. (2013) Curcumin enhances the effectiveness of cisplatin by suppressing CD133+ cancer stem cells in laryngeal carcinoma treatment. Experimental and Therapeutic Medicine 6: 1317-21.
  33. Zhu Y, Wu H, Wang PP et al. (2013) Dietary patterns and colorectal cancer recurrence and survival: a cohort study. BMJ Open3: e002270.
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