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Polyphenols and phytochemicals 

 What are phytochemicals       Classification       Polyphenols and cancer       Mechanisms of action       Enhancing their effect

     

What are phytochemicals?

Phytochemicals are the gifts from nature, which are responsible for the colour, taste and aroma of plant based foods. As well as these pleasant attributes, they protect us from environmental and ingested carcinogens and have anticancer properties. It is not a surprise then that the World Cancer Research Fund and other academic bodies, report that individuals eating phytochemical-rich foods have a significantly lower risk of cancer or relapse after treatments [WCRF].

This article provides an overview of the major classes of phytochemicals, particularly polyphenols, with examples of their common food sources. It highlights the international evidence for their anti-cancer mechanisms of action and other clinical benefits, as well as discusses the pros and cons of concentrating them into nutritional supplements to harness and boost their health benefits.

There is a wide range of dietary phytochemicals, but one of the largest and well-known groups being the polyphenols. 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. 


Classification of phytochemicals

There are four major groups of phytochemicals:

  • The polyphenols which can be subcategorized as the flavonoids, phenolic acids and other non-flavonoid polyphenols.
  • The terpenoids,which can be subcategorized as the carotenoids and non-carotenoid terpenoids
  • The thiols, which includes the glucosinolates, allylic sulfides and non-sulphur containing indoles
  • A miscellaneous category with some properties within these 3 groups e.g. the betaines,chlorophylls and capsaicin.

1. The Polyphenols

Flavonoids:

  • Flavonols;quercetin, kaempferol (onions, kale, leeks,broccoli, buckwheat, red grapes, tea, apples)
  • Flavones; apigenin, luteolin (celery, herbs, parsley chamomile, rooibos tea, capsicum pepper)
  • Isoflavones; genistein, daidzein, glycitein (soya, beans, chick peas, alfalfa, peanuts)
  • Flavanones; naringenin, hesperitin (citrus fruit)
  • Anthocyanidins (red grapes and blueberries, cherries, strawberries blackberries,raspberries, tea)
  • Flavan-3-ols (tannins) ;catechins, epicatechin, epigallocatechingallate (tea, chocolate, grapes)
  • Flavanolols; silymarin, silibinin, aromadedrin (milk thistle, red onions)
  • Dihydrochalcones; phloridzin,aspalathin (apples, rooibos tea).

Phenolic acids

  • Hydrobenzoic acids; gallic acid, ellagic acid, vanillic acid (rhubarb, grape seed, raspberries, blackberries, pomegranate, vanilla, tea).
  • Hydroxycinnamic acids; ferulic acid, P-coumaric acid, caffeic acid, sinapic acid (wheat bran, cinnamon, coffee, kiwi fruit, plums, blueberries)

Other non-flavonoid polyphenols

  • Other tannins (cereals, fruits berries, beans, nuts, wine cocoa)
  • Curcuminoids, curcumin (Turmeric)
  • Stilbenes;cinnamic acid, resveratrol (grapes, wine,blueberries, peanuts, raspberries)
  • Lignans; secoisolariciresinol, enterolactone,sesamin (grains, flaxseed, sesame seeds)

2. Terpenoids

1. Carotenoid terpenoids:

  • Alpha, beta and gamma carotene (sweet potato, carrots, pumpkin, kale)
  • Lutein (corn, eggs,kale, spinach, red pepper, pumpkin, oranges, rhubarb, plum, mango, papaya)
  • Zeaxanthin (corn, eggs, kale, spinach, red pepper, pumpkin, oranges)
  • Lycopene (tomatoes, watermelon, pink grapefruit, guava, papaya)
  • Astaxanthin (salmon, shrimp, krill, crab)

2. Non-carotenoid terpenoids

  • Saponins (chickpeas, soya beans)
  • Limonene (the rind of citrus fruits)
  • Perillyl Alcohol(cherries, caraway seeds, mint)
  • Ursolic acid (apples, cranberries, prunes, peppermint, oregano, thyme)
  • Ginkgolides (Bilobalide Ginkgo Ginkgo biloba).

3. Thiols

  • Glucosinolates; isothiocyanates and dithiolthiones (cruciferous veg such as broccoli, asparagus, brussel sprouts, cauliflower and radish 
  • Allylic sulfides; allicin and S-allyl cysteine (garlic, leeks, onions)
  • Indoles, Indole-3-Carbinol (I3C) (broccoli, brussel sprouts).

Other phytochemicals

  • Betaines found in beetroot
  • Chlorophylls found in green leafy vegetabls
  • Capsaicin found in chilli
  • Peperine in black peppers.

 


Clinical evidence for phytochemicals  against cancer

Low polyphenol rich diets have been linked to a number of degenerative chronic illnesses such as dementia, high cholesterol, arthritis, skin aging and macular degeneration [Rezai-Zadeh, Maclarty, Elmets]. On the other hand, polyphenol rich diets have been linked to both a reduced risk of developing cancer and improved outcomes after initial treatments. The most notable scientific clinical studies are summaries here:

Carotenoids found in leafy green vegetables and carrots, have been in a number of larger population studies to be linked with a lower risk of breast cancer as well as ovarian and pancreatic cancers in smokers. [Hu, Tung, Banim, Chaoyang].

Sulfuraphane and Indol 3 carbinol in broccoli and other cruciferous vegetables, such as cabbage, cauliflower, Brussel sprouts and radishesrich in have been associated with a lowerprostate cancer risk [Joseph]. Broccoli induces the anti-oxidant enzymes glutathione S-transferases which explains why it is particularly beneficial in the 50% of the population carrying a mutated glutathione gene (GSTM1)  [Heinen].

Curcuminoids found in in curcurmin, gives turmeric its yellow colour. Research has also shown that there are low rates of certain types of cancer in countries where people eat curcumin at levels of about 100 to 200 mg a day over long periods of time. A clinical trial looked at giving curcumin to patients with pre cancerous changes in the bowel show that it could stop the precancerous changes becoming cancer [CRUK]. A number of laboratory studies shows it can able to kill cancer cells and prevent more from growing. It has proven effects on breast, prostate, bowel, stomach cancer and skin cancer cells. A 2007 American study that combined curcumin with chemotherapy to treat bowel cancer cells in a laboratory showed that the combined treatment killed more cancer cells than the chemotherapy alone. 

Tannins and phenolic acids ingreen tea lower risk of breast, prostate, ovarian and oesophageal cancer particularly among smokers and alcoholics [Sun, Wu 2006]. High green teaintake after cancer reduced relapse rates both for breast [Ogunleye] and colorectal cancer [Zhu]. It also decreased the abnormal white cell count in 30% of patients with chronic leukaemia and reduced the levels of several proliferation factors, as well as  PSA among men with prostate cancer [Shanafelt].

Ellagic acidis found in pomegranate, which in phase II and randomised studies involving men with prostate cancer, itslowed the rate PSA progression and other markers of cancer progression especially if given in a combination of other polyphenol rich foods as a supplement [Paller, Thomas, Carducci, Pantuck].

Lignans- Women with breast cancer who had the highest serum lignan levels, reflecting good intake of legumes, cereals, nuts and soya, were reported to have the lowest risk of death [Buck 2011]. Likewise, a lignan and polyphenol rich diet was associated with a lower colorectal cancer relapse rate [Zhu].

Isoflavonesand flavanonesfoundpulses and soy productsare linked with lower breast and prostate cancer especially if they had regular intake from childhood [Song-yi]. The largeShanghai Breast Cancer Survival Study showed that women with the highest intake of the phytoestrogenic polyphenols isoflavones and had a 29% lower risk of relapse and death [Boyapati].

Lycopene found in colourful fruits and tomatoes has been  linked to lower prostate cancer risk [Giovannucci]

Flavonoids such as quercetin found in onions, have been shown to reduce theincidence of numerous cancers particularly those arising from the lung in smokers [Knekt, Le Marchand].

Anthoxanthins, in dark chocolate, have been reported to lower the risk of colon cancer [RodrŪguez-Ramiro]

Phenolic and caffeic acids in coffee has been shown to reduce the risk of all types of skin cancers [Song, Loftfield] and colon cancer growth in laboratory studies [Kang].

Zeaxanthin rich foods, found leafy green vegetables, reduced the subsequent new skin cancer formation after treatment of a primary lesion in a large Australian study [Heinen].

 


Potential anti-cancer mechanisms of phytochemicals?

1. Antioxidant properties The most quoted cancer prevention mechanism is via their antioxidant activity, elicited either through direct free radical absorption or through induction of antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione via a variety of molecular mechanisms [Reuland, Johnson].  One of these mechanisms is via activation of Nrf2, which switches on genes that code for antioxidant as well as detoxification enzymes  [Reuland, Johnson]. Phytochemicals have also been shown to inhibit the conver≠sion of pro-carcinogens to their electrophilic (DNA damaging), particularly the thiol class such as sulforaphane [Gasper, Johnson]. A number clinical studies involving known common carcinogens have highlighted the antioxidant properties of phytochemicals. One experiment involved the known house-hold carcinogen triclocarban, commonly found in detergents and cleaning agents. 

Healthy cells exposed to triclocarban tend to mutate into pre-malignant cells, however, the amount and rate of carcinogenesis was significantly reduced by adding curcumin to the petri disk culture feeds [Sood].  In another study, volunteers who ate a diet rich in kaempferol were found, on serum and urine analysis, to haveimproved SOD activity and higher urinary concentration of these polyphenols [Kim]. Rats exposed to cigarette smoke given indole-3-carbinol, a phytochemical rich in cruciferous vegetables, had a lower lung cancer rate than those not given idole-3-carbinol [Morse 1990]. Subjects eating a meal of onions, which increased their serum levels of quercetin, demonstrated decreased levels of oxidative metabolites including 8-hydroxydeoxyguanosine (8-OHdG) a marker of DNA damage and repair [Boyle, Wu]. A clinical study from Singapore gave Chinese smokers 170g of watercress a day, rich in the indole-3-carbinol, and found a similar effect on urinary markers of DNA damage [Hecht]. Marinating meat in rosemary and thyme, has been reported to reduced the serum levels of carcinogenic heterocyclic amines (HCA) by 87% compared to subjects who eat the meat unseasoned [Smith].

2. Reducing chronic inflammation. Another key anti-cancer mechanism of phytochemicals appears to be their ability to reduce inappropriate inflammation. It is now well established that inflammation is intimately involved in the cancer process, particularly in the promotion and progression stages of cancer. Inflammation is closely associated with oxidative stress and activation of NF-kappa B family of transcription fac≠tors. These factors regulate more than 150 genes involved in mechanisms of cell survival and these target genes are not just pro-inflammatory but also oncogenic. Numerous phytochemicals have been shown to inhibit NF-kappa B signaling particularly the green tea polyphenol epigallocatechin-3-gallate (EGCG), curcumin and bilberries [Karlsen].

3. Direct biological effects. More recently, it has been discovered that phytochemicals have an affect on several cancer process through modulation of cellular and signalling events involved in growth, invasion and metastasis [Johnson]. Pomegranate, for example, 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 [Retitig, Malik]. It has also been reported to inhibit processes involved in cancer metastasis in a study involving oestrogen sensitive and resistant breast cancer cell lines showing increased markers of cell adhesion and migration in cancer but not normal cells [Lansky]. In another studying it inhibited a chemokine that attracts breast cancer cells to the bone [Rocha].  Curcumin slows cancer cell growth by blocking the cell cycle, increasing the rate of apoptosis and preventing the invasion and migration of cells [Somasundaram, Zhang, Dorai, Iqbal]. It has also been found to halt the growth of stem cells that give rise to breast cancer without harming normal breast stem cells [Handler]. 

Curcumin is able to modulate miRNA expression in breast cancer cells leading to a reduced expression of Bcl-2 [Yang, 2010] and stabilisation of tumour suppressor gene in colorectal cancercell lines[Mudduluru]. Green tea, rich in epigallocatechingallate (EGCG), has demonstrated significant reduction of several factors that promote cancer cell growth, de-differentiation and angiogenesis [Shanafelt, Pietinen, Voorrips]. It has also been shown to block ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis [Yang, Liao). Broccoli sparks numerous genetic changes, activating cancer suppressor genes and switching off promotion genes [Moysich]. Resveratrol has demonstrated epigenetic regulatory properties which influence regulate cell survival and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factor [Chen].

4. Phytochemical (Hormonal effects) Some polyphenols and other phytochemicals are also able to influence cancer via a hormonal mechanism. Phytoestrogenic compounds, most notably isoflavones and lignans found in soy products, legumes and to a less extent some cruciferous vegetables, weakly bind to the oestrogen receptor without stimulating proliferation of the cells yet at the same time blocking the binding of more harmful oestrogens including those produced endogenously [Smith].  This explains why in the,Shanghai Breast Cancer Survival Study women with the highest intake of isoflavones and flavanones  rich foods  had a lower risk of death [Boyapati]. In men, phytoestrogenic compounds have been shown to affect 5 alpha reductase lowering endogenous testosterone levels. This may partly explain why men who eat phytoestrogenic foods such as beans and pulses have a lower risk of prostate cancer.


Can concentrating foods into supplements enhance their benefits?

If certain foods have anti-cancer effects, then it is not unreasonable to hypothesise that concentrating them into a pill may be a good way to supplement individuals with a poor diets or further enhance the benefits in those whoís diets are already adequate.  There are two main categories supplements commercially available. The first involves chemicals extracted from food or made synthetically such as minerals and vitamins, the second involves purifying and concentrating whole foods:

Vitamins and mineral supplements:

The majority of studies, to date, have evaluated extracted chemicals such as vitamins and minerals. Some have shown a benefit. For example, a recent meta-analysis of studies reported that women who took supplements providing an average daily intake of vitamin C over 100mg had a reduced risk of breast cancer relapse [Harris]. The SU.VI.MAX study randomised French adults to a single daily capsule of ascorbic acid, vitamin E, beta carotene, selenium, and zinc, or a placebo and found no reduction in mortality or cancer specific mortality overall [Hercberg] although a further analysis in men found a reduction in the risk of prostate cancer. The authors postulated this difference between the sexes was related to French men having a lower baseline micro-nutrient status [Meyer 2005].  A major trial of selenium and vitamin supplements in a poor region of China demonstrated reduced risks of oesophageal cancer; at the time this population were known to have widespread micro-nutrient deficiencies [Blot].

Unfortunately, most other studies of vitamin and minerals or other extracted nutrients have shown no benefit or have actually shown an increased risk of cancer.For example, the CARET study found that beta carotene and retinol increased the risk of lung cancer [Omenn]. The Health Professionals Follow up study (HPFS) which followed the lifestyle habits of 51,529 male professionals for over 15 years found that men who took very high doses of zinc (>100mg/day), or took it for long durations were more than twice as likely to develop advanced prostate cancer compared with controls [Leitzmann]. The randomised SELECT study showed an increased prostate cancer incidence with vitamin E and selenium supplementation [Klein]. A further analysis of the HPFS found that of the 4,459 men who had developed prostate cancer those who took selenium supplementation of ≥ 140 μg/d after diagnosis were associated with a 2.60-fold greater risk of prostate cancer mortality [Kenfield]. 

The negative effects of vitamin E and beta carotene were once again demonstrated in the ATBC study which found them to increase lung cancer risk, although subsequent analysis showed men with pre-intervention low plasma levels of beta-carotene had a lower prostate cancer risk following supplementation and those with high levels had a higher risk, particularly in smokers[Heinonen]. This u-shaped distribution of risk was also observed in the EPIC study where those with folate-deficient diets and those with the highest intake both had a higher risk of cancer [Chuang]. These data have prompted organisation such as the National Cancer Institute to issue statements stating that long term vitamin and mineral supplements should ideally be given to correct a known deficiency [Greenwald] which is rarely routinely detected unless individuals have self funded micro-nutrient analysis (link).

Whole food supplements:

More recently academic attention has turned towards the evaluation of concentrated whole food supplements, particularly foods rich in polyphenols and other phytochemicals such as herbs, spices, green vegetables, teas and colourful fruits which have appeared to be beneficial in environmental cohort studies. Despite some initial encouragement from smaller evaluations [Giovanni], studies of extracted lycopene or genistein given on their own in more scientifically robust analysies have not demonstrate a benefit for either prostate cancer or benign prostatic hypertophy [Barber, Clark, Brasky, Spentzos], nor were there a links with the reduction in the risks of breast cancer with regular intake [Hu]. Of more concern, a randomized study from Memorial Sloan Kettering reported that serum taken from women who had take very high dose soy supplementation (25.8 g twice a day) added to laboratory tumour cells caused them to proliferate faster and overexpress the tumorigenic growth factors [Shike]. This supports the notion that phytoestrogen foods are healthy but concentrated them into strong supplements is not recommended.

On the other hand, no study of non-phytoestrogenic foods supplements, have shown any detrimental effects on cancer outcomes and some have beneficially influences progression rates, as highlighted above [Brasky,ShrŲder,Shanafelt, Carducci]. Interesting one of the most popular supplements, Saw Palmetto, despite an effect in early small studies, showed no benefit for prostate cancer or benign prostatic hypertrophy in the largest randomised evaluation [Bent]. Likewise, another popular supplement lycopene despite similar suggestions from smaller non-randomised trials [Clark, Giovanucci] showed no benefits in a more robust evaluation.

So far, the largest trial analysing phytochemical-rich food extracts wasthe National Cancer Research Network Pomi-T study. This study combined four different food types (pomegranate, green tea, broccoli and turmeric) in order to provide a wide spectrum of synergistically acting nutrients, whilst at the same time avoiding over-consumption of one particular phytochemical. It involved two hundred men, with localised prostate cancer managed with active surveillance or watchful waiting experiencing a PSA relapse following initial radical interventions.

The results, announced as an oral presentation at the American Society of Clinical Oncology conference Chicago, showed a statistically significant, 63%,reduction in the median PSA progression rate compared to placebo in both men on active surveillance and experiencing a PSA relapse post treatment. A further analysis of MRI images, showed the cancers size and growth patterns correlated with PSA changes, excluding the possibility that this was just a PSA rather than tumour effect [Thomas 2016]. 

It was well tolerated, apart from some mild loosening of the bowels in 10% of men, and there was no effect on testosterone levels. At 6 months, significantly more men opted to remain on surveillance rather than proceeding to expensive radiotherapy, surgery or medical castration which can cause unpleasant effects such as depression, hot flushes, weight gain, osteoporosis, erectile dysfunction [Thomas].

A number of other RCTís involving whole food phytochemical rich supplement have demonstrated benefits for some of the distressing symptoms common after cancer treatments such as fatigue [Barton] and urinary infections [Bonetta]. There are currently over 10 on-going studies registered with the National Institute of Health.In the UK, the Institute of Preventative Medicine have plans to include the Pomi-T supplement into the next national prostate cancer prevention study. This study will be recruiting men with a higher genetic risk of prostate cancer identified in the national RAPPER study co-ordinated from the Institute of Cancer Research. Further trials are being designed involving men with prostate cancer already on androgen deprivation therapy and individuals with skin, colorectal and bladder cancer. In the meantime, a trial is passing through the regulatory process to investigate whether the natural anti-inflammatory properties of these ingredients could help joint pains after breast cancer.  

Conclusion

There is increasingly convincing evidence to show that phytochemicals not only do they improve our daily lives by helping our food taste, smell and look appetizing they reduce our risk of cancer but help people living with and beyond treatments. Living well programmes, slowly being introduced in the UK, are beginning to highlight the importance of phytochemical rich diets, along side other lifestyle factors largely being driving by the National Survivorship Initiative and guidelines from influential organisations such as American Society of Clinical Oncology [ASCO].Going a step further and concentrating these foods or extracted elements of these foods into nutritional supplements gives an opportunity to boost their beneficial anti-cancer effects but have their pitfalls. Studies of concentrated minerals, vitamins and phytoestrogenic supplements have reported detrimental effects although no study has reported detrimental effects of whole non-phytoestrogenic food supplements and some significant advantages. Despite these potential benefits and reports that over 60% of patients living with and beyond cancer take nutritional supplements, oncologist have been reluctant to discussing theirpros and cons due to a lack of RCT from academic institutions [Uzzo, Bauer].  Hopefully this trend will change particularly following the success of the Pomi-T study [Thomas].

 

Table 2 Summary

Higher intake of phytochemical rich foods such as colourful fruit vegetables, herbs, pulses, spices and teas is associated with a lower risk of cancer and relapse after treatments.

Their anti-oxidant properties help protect our DNA from ingested or environmental carcinogens.

Phytochemicals, particularly polyphenols have direct anti-cancer mechanism of action via inflammation, modulation of cellular and signaling events involved in growth, invasion and metastasis.

Concentrating element of foods such as mineral, vitamins and phytoestrogenic polyphenols to potentially boost their health effects have largely been unsuccessful in preventing cancer in clinical trials

Whole food phytochemical rich supplements have demonstrated significant benefits in phase 2 and the well conducted  UK Pomi-T RCT and their true potential is been evaluated in ongoing studies

 

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This book, with a foreword from Paula Radcliffe, contains robust research based guidance showing how diet, exercise and other lifestyle changes can; help avoid cancer, help you cope with treatments side effects; slow progression and prevent relapse ..more Micro-nutrient testing empowers you to make dietary choices specific to your personal make up. This Cancer Risk Nutritional Profile, analyses over 50 of the essential blood micro-nutrients and recommends specific dietary and supplement advice to ensure you have the best possible nutritional status to help fight cancer and aid recovery from treatments..more