A review of polyphenols in foods such as broccoli, pomegranate, green tea, and turmeric and their strong health benefits, by Professor Robert Thomas; and how his understanding led him to research a polyphenol-rich compound he calls Pomi-T in clinical trials against prostate cancer.
Polyphenols - fighting illness and cancer
In this article we look at the strength of polyphenols in fighting illness and particularly cancer that led to producing and then testing in Clinical Trials a product launched as Pomi-T, which has been shown to reduce PSA readings in Prostate Cancer patients. (By Professor Robert Thomas, a consultant oncologist specialising in Prostate Cancer at Bedford and Addenbrooke’s Cambridge University Hospitals)
Go to: Pomi-T: buy as a food supplement
An increasing number of well-conducted studies are linking natural plant based phytochemicals, particularly polyphenols, with a lower risk of chronic illnesses such as dementia, high cholesterol, arthritis, skin aging and macular degeneration (Rezai-Zadeh 2008, Maclarty 2009). The evidence for their impact on cancer incidence and relapse is also becoming increasingly convincing as more clinical research is emerging.
Cancer prevention - breast, pancreatic and prostate cancers
There are now several large prospective cohort studies which demonstrate that people who eat diets rich in polyphenols have a lower risk of cancer. Links are especially strong for breast, pancreas, colorectal, oesophagus, ovarian and prostate cancers (Giovannucci, Chaoyang, Joseph, Wu, Tung Wu, Tung, Banim, Hu, Sun). For example, a large meta-analysis recorded a significant relationship between the incidence of breast cancer and a higher consumption of carotenoid-rich foods such as leafy green vegetables, carrots, broccoli and asparagus (Hu 2012). Another study linked the regular long term intake of antioxidant-rich foods such as herbs, spices, tea, fruit and vegetables with a lower incidence of pancreatic cancer and the Health Professional Study linked colourful fruits, berries and tomatoes with a lower risk of prostate cancer (Giovanni). A recent study from South Carolina linked flavonoid-rich foods such as beans, pulses and legumes with a lower risk of an aggressive type of prostate cancer (Spect 2012). Although there is still a lack evidence from randomised trials but the sheer number of cohort studies with the same conclusions are certainly convincing.
Benefits of phytochemical-rich foods after cancer has developed
Breast cancer and healthy foods - The evidence for the benefits of polyphenol-rich healthy foods does not stop after a diagnosis. A study involving 1490 breast cancer survivours from the USA showed that those regularly taking higher than the government recommended 'five fruits and vegetable a day' had a third lower breast cancer recurrence risk especially if combined with regular physical activity (Pierce 2009). Another study showed that women with breast cancer with the highest lignan levels in their blood stream reflecting good intake of foods such as legumes, cereals, cruciferous vegetables, coffee and soy had the lowest risk of death intake (Buck 2011). The Shanghai Breast Cancer Survival Study of 5,042 Chinese women patients showed that those with the highest intake of isoflavones and flavanone rich foods such as soya had a 29% lower risk of death (Boyapati 2005). A major cohort study showed that regular green tea consumption was associated with a lower breast cancer recurrence (Ogunleye 2010).
Skin cancer - An Australian study involving individuals who had already been treated for the common types of skin cancer occurring later in life (Basal cell carcinoma or squamous cell carcinoma) showed that those who had high lutein zeaxanthin (leafy green vegetables) intake had a lower rate of new cancer formation (Heinen 2007).
Prostate cancer - Men with prostate cancer randomised to a lifestyle programme, including healthy eating had a slower rate of PSA progression (Ornish). A phase II study reported that the PSA doubling time (PSAdt) significantly prolonged in men given 200ml pomegranate juice a day (Pantuck 2006).
A number of other studies evaluating the impact of polyphenols after cancer are underway. The largest and probably most comprehensive of these is the UK’s DietCpmpyF prospective trial involving 3159 women treated for breast cancer (Swann et al 2013).
Anti-cancer mechanisms of phytochemicals
The most quoted anti-cancer mechanisms of phytochemicals is via an antioxidant pathway either by inducing the antioxidant enzymes such superoxide dismutase, catalase and glutathione or by absorbing free radicals directly. Either way, their regular consumption protects the DNA from oxidative damage caused from ingested or environmental carcinogens. A good example of this was demonstrated in a laboratory study involving cancer cell lines. Exposed to a known house hold carcinogen (Triclocarban), they rapidly mutate into cancer cells. On the other hand, adding curcumin to the culture feed significantly reduced the amount and rate of carcinogenesis (Sood S). Another study conducted by the Food Safety Consortium at the University of Arkansas showed that marinating meat in rosemary and thyme reduced the heterocyclic amines (HCA) by 87%. This and other carcinogens produced by grilling at high temperatures are known to increase the risk of prostate cancer in human and laboratory studies (Smith S).
In addition to their antioxidant absorption capacity, certain phytochemicals are able to bind to the oestrogen receptor. This phytoestrogenic compounds, most notably isoflavones and lignans are found in soy products, legumes, pulses and cruciferous vegetables, which weakly bind to the oestrogen receptor without stimulating proliferation of the cells yet at the same time blocking the binding of more harmful oestrogens - this includes those produced by your own body or those ingested or absorbed such as xenoestrogens and metaloestrogens. In men they have been shown to affect 5 alpha reductase lowering endogenous testosterone levels (Smith S).
An increasing number of research laboratories are conducting experiments which are revealing significant beneficial effects of polyphenols on the fundamental mechanism of cancer growth, invasion and metastasis. For example:
Pomegranate, with a high concentration of 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 also has been reported to inhibit processes involved in cancer metastasis in a study using oestrogen sensitive and resistant breast cancer cell lines, increasing markers of cell adhesion and migration in cancer but not normal cells (Lansky) and in another it inhibited a chemokine that attracts breast cancer cells to the bone and expression of a gene that is important in epithelial-to-meshenchymal transitions (Rocha).
Green tea - rich in epigallocatechin gallate (EGCG), blocks ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis (Yang, Liao). Green tea, in laboratory studies, has demonstrated significant reduction of several factors that promote breast and prostate cancer cell growth, de-differentiation and angiogenesis (Shanafelt, Pietinen, Voorrips).
Broccoli - rich in isothiocyanate (ITCs) and its metabolite sulforaphane, have been found to inhibit growth and promote apoptosis of cancer cells (Sarkar). One study found that broccoli sparks numerous genetic changes, activating cancer suppressor genes and switching off promotion genes (Moysich). 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) (Joseph, Heinen).
Curcumin, rhich gives turmeric its yellow colour, slows cancer cell growth by blocking the cell cycle, increasing the rate of apoptosis, preventing the invasion and migration of cells (Somasundaram, Zhang, Dorai T Iqbal M). Research conducted at the University of Michigan also found that turmeric helped halt the growth of stem cells that give rise to breast cancer without harming normal breast cells (Handler N).
Can concentrating foods into supplements enhance their anti-cancer effect?
If certain foods have anti-cancer effects, then it is logical to extrapolate that concentrating them into a pill may help correct for poor diets or further enhance the benefits in those whose diets are already adequate. Cancer survivours are attracted to the potential health benefits of food supplement with over 70% reporting regular intake (Bauer 2012, Uzzo 2004). There are two main categories of supplements commercially available. The first involves chemicals extracted from food or made synthetically. The second involves concentration of a whole polyphenol rich food. 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 showed that women who took supplements providing an average daily intake of vitamin C over 100mg had a reduced risk of breast cancer relapse [Harris 2014. 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 difference in sex was related to French men having a lower baseline micro-nutrient status (Meyer 2005). For the same reason, a major trial of selenium and vitamin supplements in poor regions of China demonstrated reduced risks of oesophageal cancer as, at the time this population were known to have widespread micronutrient deficiencies( Blot 1993).
Unfortunately, most other studies have shown no benefit or were actually linked to an increased risk of cancer. For example, the CARET study found that beta carotene and retinol increased the risk of lung cancer (Omenn). Likewise, the ATBC study found that alpha vitamin E and beta carotene increased lung cancer risk but in a subsequent analysis men with pre-intervention low plasma levels of beta-carotene had a lower prostate cancer risk following supplementation but those with high levels had a higher risk particularly in smokers (Heinonen). This u-shaped distribution of risk was also observed the EPIC study a U-shaped with those with diets deficient in folate and those taking the highest folate intake both having a higher cancer risk (Chuang 2011). Two other Scandinavian studies demonstrated a higher cancer risk following vitamin B supplementation intake (Ebbing 2009, Figueiredo 2009). A double blind RCT trial involving men with progressive prostate cancer showed no benefit for a supplement containing salicylate alone versus salicylate plus vitamin C, copper and manganese gluconate (Thomas 2009). In the HPFS, men who took zinc of more than 100mg/day or for long durations were more than twice as likely to develop advanced prostate cancer compared with controls (Leitzmann 2003). The SELECT study showed an increased prostate cancer incidence with vitamin E and selenium (Klein, 2009). A study from Australia showed that individuals who took beta carotene and Vitamin E supplements had a higher rate of new skin cancer formation [Heinen 2007). These data have prompted organisations such as the National Cancer Institute to issue statements stating that long term vitamin and mineral intakes are discouraged unless correcting a known deficiency (Greenwald) and micro-nutrient testing is now becoming more widely available (cancernet.co.uk).
Despite some initial encouragement from smaller evaluations of extracted phytochemicals, studies of Saw Palmetto or Genistein given on their own in more scientifically robust analyses have not demonstrated a benefit for either prostate cancer or benign prostatic hypertophy (Brasky 2011, Brent 2006, Spentzos 2003). Likewise, despite the initial enthusiasm for lycopene-containing foods from cohort observations (Giovanni), the two most recent RCT’s of lycopene extracts amoung men on AS or WW found no difference in PSA progression [Barber NJ, Clark PE), nor were there any links with the reduction in the risks of breast cancer with regular intake (Hu 2012).
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Concentrated whole Foods may be more important than supplements
More recently scientific attention has turned towards the evaluation of concentrated whole foods, particularly those rich in polyphenols and other healthy phytochemicals particularly herbs, spices, green vegetables, teas and colourful fruits. A study of pomegranate seed extract from John Hopkins which gave men a pill containing pomegranate seed extract and found a reduction in PSA progression rate (Carducci). The Mayo Clinic found that green tea extract decreased the abnormal white cell count in 30% of patients with chronic leukaemia and a study from Louisiana University reported a significant reduction in the levels of several growth factors that promote cancer as well as a reduction in PSA among participants (Shanafelt). In the VITamins And Lifestyle (VITAL) cohort study grapeseed extract was found in to be linked with a lower risk of prostate cancer following regular intake (Brasky). In a small RCT a dietary supplement containing isoflavones and natural anti-oxidant rich supplement was shown to have a reduction in cancer risk (Shröder). A series of RCT’s of polyphenol-rich foods, either on their own or in combination, has been registered the National Cancer Institute USA and are underway or recently completed.
The largest of these trials in the UK is the National Cancer Research Network Pomi-T study, led by my team - It combined four different food types (berry, vegetable, spice and leaf) in order to provide a wide spectrum of polyphenol nutrients, whilst at the same time avoiding over-consumption of one particular type. It involved over two hundred men, with localised prostate cancer managed with active surveillance or watchful waiting experiencing a PSA relapse following initial radical interventions. They were randomised to receive an oral capsule containing a blend of pure and whole pomegranate, green tea, broccoli and turmeric, or a placebo for 6 months.
This non-commercial trial was sponsored by the charity Prostate Action, approved by the National Ethics Committee, was peer reviewed by the National Cancer Research Institute (NCRI) Complementary Therapies Research Committee. The randomisation process was outsourced and the trial methodology, collection and storage of data were verified and independently audited by an external agency to ensure adherence to European Good Clinical Practice. At the end of the trial the data was externally audited for a second time to ensure there were no data inconsistencies or deviation from the trial design, before the data base was sealed and sent for blinded analysis by the statistician at Cranfield University. The UK manufacturers of the food supplement adhered to good manufacturing practice guidelines and performed in house analysis for authenticity and purity.
The study completed recruitment 10 months ahead of schedule and found a highly statistically significant, 63% reduction in the median PSA progression rate compared to placebo. 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 the request of the peer reviewers, a further analysis of tumour size, seen on MRI images, were found to correlate with PSA changes (Thomas 2014).
The oral presentation at the American Society of Clinical Oncology conference Chicago, by myself - the chief investigator Professor Robert Thomas, a consultant oncologist at Bedford and Addenbrooke’s Cambridge University Hospitals - received immediate acclaim from the 28,000 attending oncologists and Worldwide recognition from academic institutions and patient advocacy groups. It was seen as a major breakthrough for nutritional research groups, who for years has been waiting for adequately powered well designed RCT’s in this area.
A further analysis, presented at the UK’s National Cancer research Institute Conference in Liverpool has now revealed an extra benefit which could save millions for the NHS and spare numerous men the toxicity of medical treatments. In addition to PSA, the intake of Pomi-T had a significant impact on the management decisions of men in the trial. 5.9% on Pomi-T as opposed to 23.4% in the placebo group opted to leave AS or WW for more aggressive management pathways. This difference of 17.5% was highly statistically significant (Chi2 p=0.014). Some of these men had radiotherapy or surgery but most had medical castration which can cause unpleasant effects such as depression, hot flushes, weight gain, osteoporosis, erectile dysfunction (Thomas 2013). The costs of interventions can be several and include radiotherapy and surgery, the management of troublesome symptoms and the price of the drugs to induce castration cost up to £1000 a year and men can stay on them for many years as opposed to £170 a year for Pomi-T.
Despite these finding Pomi-T is still classed as a food supplement according to MHRA and EU commission guidelines so can never become a recognised medicinal product or find its way into routine management but at least this and other food supplement studies are providing data for individuals to make informed self help lifestyle choices.
Following the success of this RCT, the research trials committee have been approached by the PROVENT Trials Committee to include Pomi-T in the next national prostate cancer prevention study. This study will also be recruiting men with a higher genetic risk of prostate cancer identified in the national RAPPER co-ordinated from the Institute of Cancer research. Further trials are being designed in New York and South Africa with early prostate cancer and in the UK involving men with prostate cancer already on androgen deprivation therapy. Funding is being sought to design studies to evaluate potential benefits for individuals with skin, colorectal and bladder cancer. In the mean time, 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.
The role of Polyphenols in the cancer process is becoming more convincing
In conclusion, the role of polyphenols in the cancer process is becoming more convincing as more evidence is emerging from well conducted clinical trials. Patients with cancer should be counselled on the benefits of eating polyphenol rich foods after their initial treatments. Following the success of the Pomi-T study, researchers should hopefully be encouraged to design further RCT’s involving polyphenol rich food supplements as a low risk, low cost lifestyle strategy to potentially slow progression and reduce relapse rates.
Go to: Buy Pomi-T here
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