How can watercress reduce the risk of cancer development?
Cancer ultimately stems from damage to cellular DNA, mostly caused by some form of carcinogen (cancer causing agent) or virus. Faulty genetic material can also be inherited. If not repaired, damaged cells have the potential to proliferate uncontrollably to form a tumour. Cancerous cells may also spread to and invade other tissues (known as 'metastasis). Many diet and lifestyle factors can influence the development of cancer, a disease that is expected to affect more than I in 3 people in the UK at some stage of their lives. This section focuses on the potential benefits of watercress.
Population studies associate an increased intake of cruciferous vegetables with reduced risk of cancers at several sites (Reference 38). In 1977, one of the first papers identifying the potential of phenylethyl isothiocyanate (PEITC) to inhibit carcinogenesis (the development of normal cells into cancerous cells) in laboratory animals was published (Reference 39). In 1995, it was demonstrated that eating watercress protected smokers from a key tobacco carcinogen implicated in lung cancer (Reference 40). In 2000, UK scientists identified a number of active isothiocyanates in watercress and found that watercress extract has more powerful anti-carcinogenic activity than PEITC alone (Reference 41). ln 2007 an important study with watercress added to the few human intervention studies investigating the effects of cruciferous vegetable consumption on cancer risk (Reference 24).
Isothiocyanates - proposed anti-cancer mechanisms.
Many studies - from laboratory and cell culture studies, through animal models and into human trials - have indicated that isothiocyanates such as PEITC and MEITCs can inhibit cancer development (References 40, 41, 42, 43, 44) by preventing carcinogen activation. They do this by inhibiting phase I enzymes such as cytochrome P450s thereby stopping a potential carcinogen becoming a carcinogen. This increases the ability of cells to resist attack from carcinogens by increasing the activity of detoxifying/antioxidant enzymes known as 'phase II enzymes' such as quinone reductase, glutathione S-transferases and UDPglucuronosyltransferases. This then inhibits cell cycle progression which limits the uncontrolled growth of cancer cells and inducing apoptosis (the death of damaged or cancer cells).
Mechanisms of other Components of Watercress
Studies using a watercress extract, which resulted in antigenotoxic (reduction in damage to DNA) effects, indicating that PEITC/other isothiocyanates are not always directly identified as the potentially active components (References 29, 45, 46).
Flavonols such as quercetin can accumulate in the plasma (Reference 27) and have been shown to modulate DNA damage from genotoxins in vitro (Reference 47) and have anti-proliferative effects (Reference 48). The hydroxycinnamic acids ferulic acid and p-coumaric acid have been found to offer free radical scavenging activity, protection against DNA breakage in mammalian cells and inhibition of phase 1 enzyme activity (Reference 49).
Watercress is also a good source of lutein and beta-carotene. Lutein has been shown to have anti-carcinogenic activities in vitro (Reference 50). A placebo-controlled trial in post menopausal women by Zhao and colleagues (Reference 51) with carotenoid supplements (lutein, I3-carotene, lycopene and as mixed carotenoids, at levels achievable with diet), found a decrease in endogenous lymphocyte DNA damage as a result of the supplementation. Although borderline, a recent pooled analysis of 11 cohort studies investigating intakes of dietary carotenoids and colorectal cancer risk identified lutein plus zeaxanthin as the only carotenoids to show any significance (Reference 52).
Research from the University of Ulster
Gill OR, Haldar S, Boyd LA, Bennett R, Whiteford J, Butler B, Pearson JR, Bradbury l and Rowland I R (2007)
Watercress supplementation in diet reduces lymphocyte DNA damage and alters blood antioxidant status in healthy volunteers.
American Journal of Clinical Nutrition 85 (2), 504-510.
Gill and colleagues set out to assess the effects of eating watercress daily on biomarkers related to cancer risk. A single blind, randomised crossover study was carried out with 30 male and 30 female healthy volunteers (of which 30 were smokers) who had a mean age 33 years (range 19-55). During the treatment phase, subjects consumed one pack of raw watercress daily (85g and purchased from a local supermarket) in addition to their normal diet. During the control phase (8 weeks) subjects were asked to maintain their habitual diet. The control and the treatment phases were separated by a 7 week washout phase when subjects consumed their usual diet, with no watercress. All volunteers completed a 7 day food diary during each phase of the trial.
The effect of watercress supplementation was measured on a range of endpoints including DNA damage in lymphocytes, activity of endogenous (internal) detoxifying/antioxidant enzymes (glutathione peroxidase, superoxide dismutase) in red blood cells, plasma antioxidants (retinol [vitamin A], ascorbic acid [vitamin C], alpha-tocopherol [vitamin E], lutein, beta-carotene), plasma total antioxidant status using the FRAP assay and plasma lipid profile. Watercress leaves were analysed and found to contain a number of phenolic compounds (rutin, hydroxycinnamic acids) as well as glucosinolates. They are also known to contain good amounts of vitamin C, vitamin E, folate, beta-carotene (which can be converted to vitamin A) and lutein.
All 60 subjects completed the study and food diary, and Body Mass Index (BMI) analysis found no statistical differences in the BMI, energy intake and macronutrient intakes between the control phase and the watercress phase of the study. However, the mean intakes of dietary fibre, vitamin C, vitamin E, folate and carotene, were significantly higher during the watercress phase of the study, suggesting they were a result of the watercress supplementation.
Compared to the control phase, watercress supplementation was associated with significant reductions in lymphocyte basal DNA damage (by 17%) and in basal plus oxidative purine DNA damage (by 22.9%). Basal DNA damage in response to ex vivo hydrogen peroxide was reduced by 9.4%. Therefore, watercress supplementation not only reduced the level of DNA damage in lymphocytes, but also increased the ability of those cells to resist DNA damage caused by free radicals. Beneficial changes seen after watercress intervention were of greater magnitude and more significant in smokers. This may reflect greater toxic burden or oxidative stress amongst the smokers, as smokers were also found to have a significantly lower antioxidant status at the start of the study compared to the non-smokers.
Plasma lutein and beta-carotene were significantly increased by 100% and 33% respectively after watercress supplementation. However, no significant changes were observed for plasma concentrations of alpha-tocopherol, retinol, ascorbic acid or in the total antioxidant potential of plasma (FRAP value). Lipid profiles (LDL, HDL, total cholesterol) were unaffected by watercress consumption, with the exception of plasma triglyceride concentration, which showed a decrease of around 10% after watercress supplementation, compared to the control phase. In response to watercress, red blood cell glutathione peroxidase and superoxide dismutase activity did not change significantly in the total study population.
Effects of watercress consumption on blood levels of lutein (100% increase)
The exact mechanisms causing the antigenotoxic (anti-DNA damaging) effects found in this study due to watercress supplementation are not clear, but may be related to antioxidant status. A decrease in endogenous lymphocyte DNA damage as a result of carotenoid supplementation has recently been demonstrated (Reference 5I). Therefore, increases in the in vivo concentrations of lutein and beta-carotene may contribute to the decrease in DNA damage levels in lymphocytes observed in the present study.
Watercress contains phenolic compounds and high concentration of glucosinolates, which may have also contributed to the antigenotoxicity observed in lymphocytes as a result of watercress supplementation. However, in this study consumption of watercress had no effect on antioxidant enzymes such as glutathione peroxidase or superoxide dismutase activity. Other potential mechanisms of the antigenotoxicity observed as a result of watercress supplementation could have been due to changes in glutathione S-transferase activity as has been previously observed with cruciferous vegetables.
The authors concluded that the result supports the theory that consumption of watercress can be linked to a reduced risk of cancer via decreased damage to DNA and possible affects on antioxidant status by increasing levels of plasma carotenoids.
Could watercress help prevent melanoma cancer?
We are currently working with Professor Mihalis Panagiotidis in Northumbria University. His work is focusing on Melanoma Cancer.
The challenging aspect of melanoma is that it is a highly metastatic disease and one of the most aggressive once a patient has been diagnosed with it. Moreover, despite recent improvements in treatment options, it remains an incurable disease with a poor prognosis and there is an unmet need for more effective treatments.
Professor Panagiotidis has explored the role of isothiocyanates almost exclusively in the context of melanoma prevention (by dietary means) but he is also very interested in looking at these compounds from the perspective of synthesizing new molecules which could be structurally analogous to isothiocyanates. This could suggest a novel means for a therapeutic avenue in treating the disease. However, in order to get all the appropriate approvals, he has to develop the mode of action by which isothiocyanates can combat melanoma development. In his lab, he is pursuing this by seeking to determine how these compounds regulate the epigenetic pathway which regulates the expression of genes involved in the killing of tumour cells (i.e. apoptotic cell death). If you Google Epigenetics it is a fascinating read. It was previously considered not possible in humans – plants do it all the time!
Professor Panagiotidis and others have shown a direct influence on the epigenetic pathway response by various dietary nutrients including isothiocyanates (watercress and other cruciferous vegetables), curcumin (turmeric spice), EGCG (green tea, vegetables and nuts), genistein (fava beans, soybeans, coffee), resveratrol (grapes, berries, peanuts) and a few more. This has now formed the concept of what is known as “epigenetic diet”.
Other forms of cancers can be influenced by the epigenetic pathway response in addition to melanoma. This has been shown through the work of other research groups in the field working on treatments for prostate cancer, liver, colorectal, breast, skin and more.
Professor Panagiotidis is leading a research group which conducts research on the molecular mechanisms underlying disease pathology and the role of nutrition in disease prevention. More specifically, his group is investigating the role of deregulated apoptosis and epigenetic pathways as key molecular targets underlining the pathological basis of human disease, including cancer.
In 2018 Professor Panagiotidis published a literature review ahead of his current research bringing together evidence of the role of isothiocyanates in skin cancer prevention. (Reference 94)
Regular consumption of cruciferous vegetables and associated isothiocyanates has been linked to a reduced risk of lung cancer, with stronger effects noted for GST null individuals (who therefore have no potential protection from the phase II enzymes, glutathione S-transferases) after sub-grouping according to GST genotype (References 61, 62, 63).
Anti lung cancer mechanisms for isothiocyanates have been attributed to the inhibition of phase I enzymes (Reference 63a) (so neutralizing potential carcinogens) and/or to the induction of the activity of phase II enzymes which can detoxify carcinogens. Other possible mechanisms include acting at the post initiation stage of lung tumour development via cell-cycle arrest and induction of apoptosis (Reference 64, 65).
Hecht and colleagues (Reference 40) had already observed significant benefits of PEITC for cancer protection in animals and wanted to assess its potential in humans. Unable to obtain a license for a human study using pharmaceutical PEITC, Hecht used watercress, the richest known food source. Eleven smokers volunteered to expose themselves to the lung-specific tobacco carcinogen 4- (rnethylnitrosamino)-1-(3-pyridyI)-1-butanone (NNK) for 3 days, while consuming 2 ounces (56.8 g) of watercress at each meal. The result was a highly significant increase in urinary NNK breakdown products during days 2 and 3 which correlated with the intake of PEITC from watercress during this period. This linked PEITC and watercress consumption to the metabolism and secretion/neutralization of the lung carcinogen NNK.
A number of epidemiological studies link consumption of diets rich in cruciferous vegetables with a reduced incidence of prostate cancer (References 57, 58). One prospective study found a weak association but suggested that the potential benefits of cruciferous vegetables may emerge only after many years and consumption from an early age is recommended (Reference 59).
Direct studies with watercress have not been carried out. However, mechanisms to explain positive associations with cruciferous vegetables are being investigated. PEITC, the major isothiocyanate in watercress, has recognised anti-carcinogenic effects (Reference 40). More recent in vivo work suggests a potential effect on tumour growth. After finding that in vitro exposure of human prostate cancer cells to the N-acetylcysteine (NAC) conjugate of phenethyl isothiocyanate (PEITC-NAC), significantly inhibited their growth. Chiao et al (Reference 60) assessed the in vivo affects of a PEITC-NAC supplemented diet versus a non-supplemented diet on tumours of human prostate cancer cells grafted on to mice.
After a 9 week treatment period, there was a significant reduction in tumour size in 100% of the mice on the supplemented diet. Tumour weight was reduced by 50% compared with mice on the diet without PE1TC-NAC. Mechanisms identified in this study suggest that PEITC-NAC may reduce tumour growth by inhibiting proliferation (uncontrolled cell growth) via cell cycle regulators, and inducing apoptosis (externally triggered cell death).
In 2010 research led by Professor Graham Packham at Southampton University showed that a watercress compound called Phenylethyl isothiocyanate (PEITC) interferes with the function of protein which plays a critical role in cancer development. It does this by turning off a signal called Hypoxia Inducible Factor (HIF). HIF is sent out by the tumour to normal tissues to grow new blood vessels and therefore spread. By turning off this signal the tumour is effectively starved and further growth prevented. Professor Graham Packham said: "The research shows that eating watercress may interfere with a pathway that has already been tightly linked to cancer development." (Reference 91)
More recently a study published in European Journal on Nutrition (Reference 92, 93) sought to determine the potential for watercress extracts and PEITC to protect against the DNA damage caused by ionising radiation (IR) in breast cancer cells and to be protective against radiation-induced collateral damage in healthy breast cells. The metabolic events that mediate such responses were explored using metabolic profiling.
PEITC, of which watercress is the richest natural source, enhanced the sensitivity of the breast cancer cells to Ionising Radiation increasing the effectiveness of the cancer-killing process. As an additional benefit, the powerful antioxidants in watercress-protected non-tumorigenic breast cells from radiation-induced damage. These effects were driven by changes in the cellular content of the antioxidant glutathione following exposure to PEITC and other phytochemicals in watercress. Results are supported by Professor Ravesco’s publications and the author observed a significant reduction in skin damage to patients who ate watercress daily whilst undergoing radiotherapy for breast cancer.
Epidemiological studies link cruciferous vegetable intake with a reduced risk of colorectal cancer (Reference 30). However, recent cohort studies appear to question the strength of these findings, despite plausible mechanisms for anti-carcinogenic activity of cruciferous vegetables. These inconsistencies may be explained by factors such as the sensitivity of measuring vegetable intake, amounts of cruciferous vegetables needed to be consumed to achieve an effect, and differences in response according to glutathione S-transferase genotype (sub-grouping populations according to glutathione S-transferase genotype appears to strengthen the relationship) (Reference 30).
Further supportive evidence comes from a recent investigation into potential anti-carcinogenic mechanisms for the cruciferous vegetable watercress, led by scientists at the University of Ulster (Reference 29). They showed for the first time that an extract of watercress juice can inhibit the three key stages of carcinogenesis. Namely: initiation (the DNA damage that triggers cancer cell development); proliferation (uncontrolled growth) of cancer cells; and metastasis (the spread of cancer cells).
The study involved incubating human colon cancer cells (HT29) with watercress extract, prepared using watercress bought from local supermarkets. The cells were then either exposed to toxins (H202, 4-Hydroxy nonenal and faecal water) known to promote the DNA damage and abnormal changes that initiate carcinogenesis, or had their ability to proliferate assessed. Metastasis (their ability to invade tissues) was assessed by studying attachment and penetration of HT 115, human colorectal adenocarcinonna, cells through Matrigel.
The watercress extract significantly inhibited DNA damage induced by oxidative stress from H202 (by 28%) and by faecal water (by 19%), delayed the cell cycle of the colon cancer cells, which in turn delays their growth, and significantly blocked the cells' invasive or metastatic actions. The study differed from many others in that it used extracts of whole watercress rather than individual phytochemicals found in watercress to test for anti-carcinogenic effects. This provided information on the overall effect of identified, and still to be identified, compounds in watercress, and how they might work together. The authors concluded that their studies support the view that watercress may be effective in helping to reduce cancer risk in humans, and further studies are warranted.
Independent peer reviewed research papers
Watercress supplementation in diet reduces lymphocyte DNA damage and alters blood antioxidant status in healthy adults
Chris IR Gill, Sumanto Haldar, Lindsay A Boyd, Richard Bennett, Joy Whiteford, Michelle Butler, Jenny R Pearson, Ian Bradbury, and Ian R Rowland
Phenethyl Isothiocyanate Inhibits Angiogenesis In vitro and Ex vivo
Dong Xiao and Shivendra V. Singh
7-Methylsulfinylheptyl and 8-methylsulfinyloctyl isothiocyanates from watercress are potent inducers of phase II enzymes
Peter Rose, Kathy Faulkner, Gary Williamson and Richard Mithen