Carotenoids and Cancer

Introduction

Carotenoids are a broad category of hundreds1,2­ and perhaps thousands3 of phytochemicals (plant chemicals)4 that possess a long isoprene chain and a beta-ionone ring at either end. The conjugated chemical bonds in this system neutralize free radicals that cause tissue damage, inflammation, and cancer pathogenesis in animals5,6. These conjugated bonds also produce the characteristic colors of carotenoids: e.g. the orange of carrots (beta-carotene) and the red of tomatoes (lycopene).

Carotenoids can be classified along two axes: a) the ability to be converted into vitamin A and b) the presence of an oxygen atom in the molecular structure. Common carotenoids are classified along these axes in Table 1. Carotenoids that can be converted into vitamin A are "pro-vitamin A" carotenoids. These carotenoids are cleaved in half by "beta-carotene-15,15'-oxygenase" enzymes 7 to yield vitamin A, which results in twice the vitamin A potency of beta-carotene relative to other pro-vitamin A's since both halves yield vitamin A8. The vitamin A system regulates apoptosis, immune function 9, the health of surface tissues (e.g. skin)10, and light detection in the eyes11. Carotenoids, in the other axis, that possess an oxygen atom are xanthophylls while those that do not are carotenes. The presence of an oxygen in xanthophylls doubles its bioavailability12 relative to carotenes11, although, consuming carotenes with oils can equalize the bioavailability of carotenes and xanthophylls13,14.

Excessive consumption of carotenoids, through food or especially supplementation, is mostly associated with two non-toxic and reversible conditions: the yellowing of skin ("carotenosis") 15 and diminished vision. The latter is based one case of an 84-year-old woman whose vision degraded after supplementation with 16; however, her vision returned eighteen months after discontinuing the supplements 17. The most deleterious effect of carotenoids may be its hepatotoxic interaction with alcohol, similar to retinol vitamin A 18. These excessive effects, however, are in stark contrast to retinol vitamin A - from animal products - which can be fatal in meal dosages19-21, partly because of its high bioavailability 22.

Research

Discriminating science from pseudo-science and misinformation is difficult for health scientists and laymen alike, where principled arguments for diets/lifestyles can be confused can potentially inspire deleterious habits. The following essay demystifies a corner of nutritional science: the chemopreventive role of carotenoids. Many studies use serum carotenoid concentrations to mitigate error from dietary logging and the inherent subjectivity in estimating consumption 22.

Breast Cancer is genetically influenced by the BRCA1 and BRCA2 genes; however, 75-95% of breast cancer cases23 are attributed to lifestyle habits, e.g. alcohol consumption (see the alcohol consumption post). Breast cancer risk is interestingly inversely proportional with carotenoid consumption in women with BMI <25 24 and proportional in women with BMIs of > 3025. This perplexingly observation is explained by metabolic differences in obese women 26.

Lung Cancer risk diminished in non-smokers with high carotenoid consumption27 yet not with supplementation28, which suggests that corollary benefits of carotenoid-rich foods may be contributing preventative effects. Lycopene supplementation, however, diminished cancer risk27, which suggests a direct preventative effect.

Prostate Cancer is significantly reduced by lycopene29,30. Lycopene specifically augments the efficacy of prostate chemotherapy drugs by ~30-107%31! Animal-sourced vitamin A, by contrast, increased the risk of prostate cancer29.

Other Cancers are diminished by carotenoid consumption as well. Colorectal cancer rates were inversely correlated with serum carotenoid concentrations32,33. Liver cancer cells were killed by beta-carotene isolate on contact34. Kidney cancer is least frequent among people with the greatest consumption of fruits and vegetables35, and specifically men who can better absorb and process carotenoids than women26. Head and neck cancers are ~50% fatal36; yet, fruit and vegetable consumption22, specifically beta-carotene with vitamin C and fiber37, lowers the risk.

Conclusion

The aforementioned research suggests that the benefits of carotenoid consumption, particularly for non-drinkers, are profound in the context of diminished cancer risks. A preliminary estimate of diet-induced premature deaths in the USA was 678,000 in 201038, and accounted for > 5% of all cancers39 that collectively cost ~$4 billion40. The implicit public health epidemic of suffering from dietary diseases has an obvious solution: eat more colorful vegetables!

Table 1: Carotenoids and food examples categorically arranged along two axes: provitamin A, and carotene vs. xanthophyll.
The vitamin A potencies of provitamin A carotenoids are provided in parentheses relative to pure vitamin A (retinol).

Vitamin-A status Carotene Xanthophyll
Chemical Sources Chemical Sources
Yes 7 Alpha-carotene (~4%) Carrots Cryptoxanthins (~4%) Tangerines and papayas
Beta-carotene (~8%)8 Apricots, carrots, sweet potatoes,
spinach, broccoli, and butternut squash41
No Lycopene Tomatoes Lutein + Zeaxanthin Broccoli, spinach, kale, collard greens,
arugula, green peas, fennel/anise, and yellow egg yolks.
Gamma-carotene (~4%) Corn, yellow bell peppers, figs, and papaya Astaxanthin Algae, salmon skin

Table 2: Cancer reduction rates of people with the greatest carotenoid consumption/retention relative to people with the lowest carotenoid consumption/retention.
Entries without data are denoted with "--", which not significant data is denoted "NS".

Chemical Breast cancer Lung cancer Colorectal cancer Prostate cancer
Carotenes
Alpha-carotene 26%[24] 25%[27] 51%[32] --
Beta-carotene 28%[24] NS NS --
Lycopene 18%[24] 63%[27] 64%[32] 17-73% with chemotherapy[31]
Xanthophylls
Lutein NS NS NS --
Zeaxanthin NS -- NS --
Beta-cryptoxanthin BMI < 25: 30%[24] NS 56%[32] --
Astaxanthin NS -- 31%[33] --

References

  1. Rodríguez-Bernaldo de Quirós, A. & Costa, H. S. Analysis of carotenoids in vegetable and plasma samples: A review. J. Food Compos. Anal. 19, 97-111 (2006).
  2. Dagatti, M. S. et al. Protective effect of macro and micro nutrients on male lung cancer. A case-control study in Rosario, Argentina. e-SPEN 4, (2009).
  3. Yabuzaki, J. Carotenoids Database: Structures, chemical fingerprints and distribution among organisms. Database 2017, 1-11 (2017).
  4. Kaulmann, A. & Bohn, T. Carotenoids, inflammation, and oxidative stress-implications of cellular signaling pathways and relation to chronic disease prevention. Nutr. Res. 34, 907-929 (2014).
  5. Tanaka, T. et al. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci. 94, 965-973 (2003).
  6. Martínez-Sánchez, G. & Giuliani, A. Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development. J. Exp. Clin. Cancer Res. 26, 39-50 (2007).
  7. Giuliano, G., Al-Babili, S. & Lintig, J. von. Carotenoid oxygenases: cleave it or leave it. Trends Plant Sci. 8, 143-145 (2003).
  8. Simpson, K. L. Relative value of carotenoids as precursors of vitamin A. Proc. Nutr. Soc. 42, 7-17 (1983).
  9. Korichneva, I. & Hämmerling, U. F-actin as a functional target for retro-retinoids: A potential role in anhydroretinol-triggered cell death. J. Cell Sci. 112, 2521-2528 (1999).
  10. Carolyn D. Berdanier, L. A. B. Advanced Nutrition: Macronutrients, Micronutrients, and Metabolism. (CRC Press, 2021).
  11. McGuire, M. & Beerman, K. A. Nutritional Sciences: From Fundamentals to Food. (Cengage Learning, 2022).
  12. Huo, T., Ferruzzi, M. G., Schwartz, S. J. & Failla, M. L. Impact of fatty acyl composition and quantity of triglycerides on bioaccessibility of dietary carotenoids. Journal of Agricultural and Food Chemistry vol. 55 8950-8957 (2007).
  13. Knockaert, G., Lemmens, L., Van Buggenhout, S., Hendrickx, M. & Van Loey, A. Changes in β-carotene bioaccessibility and concentration during processing of carrot puree. Food Chem. 133, 60-67 (2012).
  14. Verkempinck, S. H. E. et al. Kinetic approach to study the relation between in vitro lipid digestion and carotenoid bioaccessibility in emulsions with different oil unsaturation degree. J. Funct. Foods 41, 135-147 (2018).
  15. Granado-Lorencio, F., Blanco-Navarro, I., Pérez-Sacristán, B. & Hernández-Álvarez, E. Biomarkers of carotenoid bioavailability. Food Res. Int. 99, 902-916 (2017).
  16. Beaulieu, R. A., Warwar, R. E. & Buerk, B. M. Canthaxanthin Retinopathy with Visual Loss: A Case Report and Review. Case Rep. Ophthalmol. Med. 2013, 1-4 (2013).
  17. Hueber, A., Rosentreter, A. & Severin, M. Canthaxanthin retinopathy: Long-term observations. Ophthalmic Res. 46, 103-106 (2011).
  18. Leo, M. A. & Lieber, C. S. Alcohol, vitamin A, and β-carotene: Adverse interactions, including hepatotoxicity and carcinogenicity. Am. J. Clin. Nutr. 69, 1071-1085 (1999).
  19. Myhre, A. M. et al. Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am. J. Clin. Nutr. 78, 1152-1159 (2003).
  20. Leo, M. A. & Lieber, C. S. Alcohol and vitamin A. Gale Acad. OneFile 13, 250+ (1989).
  21. Carpenter, T. O. et al. Severe hypervitaminosis A in siblings: Evidence of variable tolerance to retinol intake. J. Pediatr. 111, 507-512 (1987).
  22. Sivakumar, B. & Reddy, V. Absorption of labelled vitamin A in children during infection. Br. J. Nutr. 27, 299-304 (1972).
  23. Cartmel, B., Bowen, D., Ross, D., Johnson, E. & Mayne, S. T. A randomized trial of an intervention to increase fruit and vegetable intake in curatively treated patients with early-stage head and neck cancer. Cancer Epidemiol. Biomarkers Prev. 14, 2848-2854 (2005).
  24. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science (80-. ). 266, 66-71 (1994).
  25. Eliassen, A. H. et al. Plasma carotenoids and risk of breast cancer over 20 y of follow-up. Am. J. Clin. Nutr. 101, 1197-1205 (2015).
  26. Eliassen, A. H. et al. Circulating carotenoids and risk of breast cancer: Pooled analysis of eight prospective studies. J. Natl. Cancer Inst. 104, 1905-1916 (2012).
  27. Tang, G., Qin, J., Dolnikowski, G. G. & Russell, R. M. Short-term (intestinal) and long-term (postintestinal) conversion of beta-carotene to retinol in adults as assessed by a stable-isotope reference method. Am. J. Clin. Nutr. 78, 259-266 (2003).
  28. Michaud, D. S. et al. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am. J. Clin. Nutr. 72, 990-997 (2000).
  29. Gallicchio, L. et al. Carotenoids and the risk of developing lung cancer: A systematic review. Am. J. Clin. Nutr. 88, 372-383 (2008).
  30. Giovannucci, E. et al. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. J. Natl. Cancer Inst. 87, 265-273 (1995).
  31. Van Hoang, D., Pham, N. M., Lee, A. H., Tran, D. N. & Binns, C. W. Dietary carotenoid intakes and prostate cancer risk: A case-control study from Vietnam. Nutrients vol. 10 (2018).
  32. Rafi, M. M., Kanakasabai, S., Reyes, M. D. & Bright, J. J. Lycopene modulates growth and survival associated genes in prostate cancer. J. Nutr. Biochem. 24, 1724-1734 (2013).
  33. Huang, J. et al. Serum carotenoids and colorectal cancer risk: A case-control study in Guangdong, China. Mol. Nutr. Food Res. 61, (2017).
  34. Yasui, Y., Hosokawa, M., Mikami, N., Miyashita, K. & Tanaka, T. Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem. Biol. Interact. 193, 79-87 (2011).
  35. Kavalappa, Y. P. et al. β-carotene isolated from the marine red alga, Gracillaria sp. potently attenuates the growth of human hepatocellular carcinoma (HepG2) cells by modulating multiple molecular pathways. J. Funct. Foods 52, 165-176 (2019).
  36. Lee, J. E. et al. Intakes of fruits, vegetables, vitamins A, C, and E, and carotenoids and risk of renal cell cancer. Cancer Epidemiol. Biomarkers Prev. 15, 2445-2452 (2006).
  37. Chang, H. P., Sheen, L. Y. & Lei, Y. P. The protective role of carotenoids and polyphenols in patients with head and neck cancer. J. Chinese Med. Assoc. 78, 89-95 (2015).
  38. Kune, G. A. et al. Oral and Pharyngeal Cancer, Diet, Smoking, Alcohol, and Serum Vitamin A and ß-Carotene Levels: A Case-Control Study in Men. Nutr. Cancer 20, 61-70 (1993).
  39. Benjamin, E. J. et al. Heart Disease and Stroke Statistics'2017 Update: A Report from the American Heart Association. Circulation vol. 135 (2017).
  40. Zhang, F. F. et al. Preventable Cancer Burden Associated With Poor Diet in the United States. JNCI Cancer Spectr. 3, 1-9 (2019).
  41. Chang, S. et al. Estimating the cost of cancer: Results on the basis of claims data analyses for cancer patients diagnosed with seven types of cancer during 1999 to 2000. J. Clin. Oncol. 22, 3524-3530 (2004).
  42. Rao, A. V. & Rao, L. G. Carotenoids and human health. Pharmacol. Res. 55, 207-216 (2007).