The precise biochemical mechanisms through which phytochemicals exert their anti-cancer effects are still being explored, as their actions are wide-ranging and complex but significant advances have been made of late in the understanding the mode of action.
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 mechanisms1,2. One of these mechanisms is activation of Nrf2, which switches on genes that code for antioxidant as well as detoxification enzymes1,2.
Phytochemicals, particularly the thiol class such as sulforaphane, have also been shown to inhibit the conversion of pro-carcinogens to their electrophilic, DNA-damaging chemicals2,3.
A number studies involving known common carcinogens have highlighted the antioxidant properties of phytochemicals:
- A good example of their protective effect was an experiment involving 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 dish culture feeds4.
- In another study, volunteers who ate a diet rich in kaempferol were found, on serum and urine analysis, to have improved SOD activity and higher urinary concentration of these polyphenols5. 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-carbinol6.
- 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 repair7,8. Quercetin supplementation has also been shown to improving mitochondrial dysfunctions induced by the toxin 3-nitropropionic acid9.
- A clinical study in Singapore gave Chinese smokers 170g of watercress a day, rich in the indole-3-carbinol, found a significant effect on urinary markers of DNA damage10.
- Finally, 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 unseasoned11.
Another key anti-cancer mechanism of phytochemicals appears to be their ability to reduce inflammation.
It is now well established that inappropriate 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 factors. 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 signalling, particularly the green tea polyphenol epigallocatechin-3-gallate (EGCG), quercetin, curcumin, caffeic acid and caffeic acid phenethyl ester and the phytochemicals within bilberries1,12.
Affecting signaling pathways in cancer
More recently, it has been reported mainly from laboratory studies that phytochemicals have an effect on several cancer processes through modulation of cellular and signalling events involved in growth, invasion and metastasis2.
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 cells13. Pomegranate extract has also been reported to inhibit processes involved in cancer meta
stasis 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 cells14. In another study, it inhibited a chemokine that attracts breast cancer cells to the bone15.
Curcumin, a substance in turmeric, slows cancer cell growth by blocking the cell cycle, increasing the rate of apoptosis and preventing the invasion and migration of cells16,17,18,19. It has also been found to halt the growth of stem cells that give rise to breast cancer without harming normal breast stem cells20. Curcumin has been shown to modulate microRNA expression in breast cancer cells leading to a reduced expression of Bcl-221 and stabilisation of tumour suppressor gene in colorectal cancer cell lines22.
Green tea, rich in epigallocatechin gallate (EGCG), has demonstrated significant reduction of several factors that promote cancer cell proliferation by inhibiting DNA synthesis, de-differentiation and angiogenesis23,24,25. It has also been shown to block ornithine decarboxylase, an enzyme that signals cells to proliferate faster and bypass apoptosis21,26. Resveratrol has demonstrated epigenetic regulatory properties that influence cell proliferation, survival and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factor17. Caffeic acid and phenethyl ester, as well as inhibiting NF-kappa B signaling, also have been shown to inhibit cell motility in vitro and inhibit metastasis of tumour models in vivo18. Luteolin, as well as inhibiting tumour growth and metastasis, inhibits epithelial mesenchymal transition, which is a basic biological process related to cancer initiation and development18.
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 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 endogenously10. This explains why in the previously mentioned Shanghai Breast Cancer Survival Study, women with the highest intake of isoflavone- and flavanone-rich foods had a lower risk of death27. 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.
- Reuland DJ, Khademi S, Castle CJ, et al. Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress. Free Radical Biology and Medicine 2013;56: 102–111.
- Johnson I. Phytochemicals and cancer. Proceedings of the Nutrition Society 2007;66: 207-215.
- Gasper AV, Al-Janobi A, Smith JA, et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. American Journal of Clinical Nutrition 2005;82: 1283–1291.
- Sood S, Choudhary S, Wang HC et al. Induction of Human Breast Cell Carcinogenesis by Triclocarban and Intervention by Curcumin. Biochemical and Biophysical Research Communications 2013;438(4): 600-606.
- Kim HY, Kim OH and Sung MK. 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 American College of Nutrition 2003;22(3): 217-223.
- Morse MA, LaGreca SD, Amin SG, et al. Effects of indole-3-carbinol on lung tumorgenesis and DNA methylation in mice. Cancer Research 1990;50: 2613-2627.
- Wu LL, Chiou CC, Chang PY, et al. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clinica Chimica Acta 2004;339(1-20): 1-9.
- Boyle SP, Dobson VL, Duthie SJ et al. Absorption and DNA protective effects of flavonoid glycosides from an onion meal. European Journal of Nutrition 2000;39: 213–223.
- Sandhir R and Mehrotra A. Quercetin supplementation is effective in improving mitochondrial dysfunctions induced by 3-nitropropionic acid: Implications in Huntington’s disease. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 2013; 1832 (3): 421-430.
- Hecht SS, Carmella SG, Kenney PM et al. 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 & Prevention 2004; 13(6): 997-1004.
- Smith JS and The Food Safety Consortium. Brush on the marinade, hold off the cancerous compounds. ScienceDaily 2007;June 28.
- Carlsen MH, Halvorsen BL, Holte K et al. The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide. Nutrition Journal 2010;9:3 doi:10.1186/1475-2891-9-3.
- Malik A, Afaq F, Sarfaraz S, et al. Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proceedings of the National Academy of Sciences 2005;102: 14813–14818.
- Lansky EP, Jiang W, Mo H, et al. Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Investigational New Drugs 2005;23: 11–20.
- Rocha A, Wang L, Penichet M et al. Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer. Breast Cancer Research and Treatment 2012;136(3): 647-658.
- Somasundaram S, Edmund NA, Moore DT et al. Curcumin inhibits chemotherapy-induced apoptosis in models of cancer. Cancer Research 2002;62(13): 3868-3875.
- Park EJ, John M and Pezzuto JM. The pharmacology of resveratrol in animals and humans. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 2015; 1852 (6); 1071-1113
- Butterfield DA and Keller J. Antioxidants and antioxidant treatment in disease. Biochimica et Biophysica Acta 2012; 1822: 615
- Zhang HN, Yu CX, Chen WW, et al. Curcumin down regulates gene NKX3.1 in prostate cancer cell lines (LNcaP). Acta Pharmacologica Sinica 2007;28(3): 423-430.
- Dorai T, Gehani N and Katz A. Therapeutic potential of curcumin in human prostate cancer. Curcumin inhibits tyrosine kinase activity of the epidermal growth factor receptor. Molecular Urology 2000;4(1): 1-6.
- Iqbal M, Sharma SD, Okazaki Y, et al. Dietary supplementation of curcumin enhances antioxidant phase II metabolosing enzymes in mice. Pharmacology & Toxicology 2003;92(1); 33-38.
- Handler N, Jaeger W, Puschacher H, et al. Synthesis of noval curcumin analogues and their evaluation as selective cyclooxygenase-1 inhibitors. Chemical & Pharmaceutical Bulletin 2007;55(1): 64-71.
- Shanafelt TD, Call TG, Zent CS, et al. Phase I trial of daily oral polyphenon E (green tea extract) in patients with asymptomatic stage 0-II chronic lymphatic leukaemia. Journal of Clinical Oncology 2009;27(23): 3808–3814.
- Yang CS, Maliakal P and Meng X. Inhibition of carcinogenesis by tea. Annual Review of Pharmacology and Toxicology 2002;42: 25-54.
- Mudduluru G1, George-William JN, Muppala S, et al. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Bioscience Reports 2011;31(3): 185-97.
- Pietinen P, Malila N, Virtanen M, et al. Diet and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes and Control 1999;10(5): 387-96.
- Boyapati SM, Shu XO and Ruan ZX. Soy food intake and breast cancer survival: a follow up of the Shanghai Breast Cancer Study. Breast Cancer Research and Treatment 2005;92: 11–7.