Chemotherapeutic Use of Curcumin in Colorectal Cancer by Thomas E. Noerper

Chemotherapeutic Use of Curcumin in Colorectal Cancer by Thomas E. Noerper

By at February 12, 2014

Summary: Rates of colorectal cancer in India are persistently lower than rates in other countries. Investigations of dietary influence on colorectal cancer rates suggest that the use of turmeric may be an important factor in these differences. Laboratory studies have confirmed anti-cancer properties in agents found in turmeric; however, obtaining a clinically useful product has been complicated by chemical properties of the key agents. Recent attempts to overcome these problems have focused on the use of nanotechnology and other more traditional methods to deliver the active agents to cancerous cells.

Epidemiological studies persistently show that rates of colorectal cancer in India are markedly lower than rates in several developed countries, including, the U.S., U.K., Canada, Sweden, and Japan.1,2  Investigations into dietary differences among cultures have given support to the hypothesis that dietary norms may play a role in the causation or prevention of colorectal cancer.1 Further studies have suggested that the frequent use of turmeric in Indian cooking may play a major role in the low rates of colorectal cancer in India.3

Turmeric comes from the root of the Curcuma longa plant, a member of ginger family that is native of the Indian subcontinent. Turmeric is the spice that gives bright yellow or orange color to many curry sauces, and it is the ingredient that makes ordinary hot dog mustard bright yellow. Turmeric has been used for many centuries by practitioners of traditional Indian, or Ayurvedic, medicine, who use it mainly for digestive ailments and skin conditions.4  In Western medical science, the most-studied component of turmeric is curcumin.

Curcumin belongs to the class of chemicals known as polyphenols and is highly biologically active.5, 6  The anti-cancer effects of curcumin are well-established over numerous studies, both in the laboratory (in vitro) and in live animals (in vivo).6  An early study demonstrating both in vitro and in vivo anticancer effects in animal models was published in India in 1985 by Kuttan et al.7  In 1999, Kawamori, Lubet et al showed the efficacy of curcumin in inhibition of tumor cell growth in an induced model of colon cancer in live rats.8  More recently, Prakobwong, Gupta et al (2011) have demonstrated the ability of curcumin to stop the growth of human liver cancer cells in an in vitro study, and even to induce cell death (apoptosis).9  In contrast to many conventional cancer chemotherapies, curcumin has negligible toxicity in humans, even at doses up to several grams per day.10

A few small-scale clinical studies with human colorectal cancer patients have been completed.6. 11  Several curcumin studies have shown decreases in cancer markers in the blood of colorectal cancer patients awaiting surgery. 6, 11 Cruz-Correa et al (2006) showed a decrease in pre-cancerous colorectal polyps.12 He et al (2011) showed a decrease in cancer-related weight loss (cachexia), an improvement in general health, and an acceleration of tumor cell death (apoptosis).13

While some positive results were obtained in these few studies, a major finding of these studies is that turmeric or curcumin taken orally results in very low, even undetectable blood levels of curcumin – a problem known as “low bioavailability.”14, 15  In patients with colorectal cancer, orally administered curcumin is able to come into direct contact with pathological tissues; however, when other parts of the body are affected, orally-administered curcumin does not reach the pathological cells through the blood stream.  This is partly due to the rapid metabolism of a portion of curcumin, as the digestive processes break down curcumin into metabolites which do have no effect on cancer cells. Because curcumin is a hydrophobic polyphenol, it is not easily absorbed from the digestive system into the blood. The portion that is not metabolized in digestion passes out of the alimentary canal with the feces. While the feces tend to show high levels of curcumin after oral administration, the urine and blood show low levels, because the curcumin would have to be absorbed from the digestive system into the circulatory system in order to show detectable levels in blood or urine.

Researchers are employing several strategies to address the bioavailability problems with curcumin. The use of piperine, found in black pepper, as an adjuvant has been found to increase bioavailability markedly.14  Piperine acts to block the metabolism of curcumin, so that more of it reaches the bloodstream.  One strategy under investigation is the use of nanoparticles as a delivery system for curcumin, in which the hydrophobic curcumin particles are encapsulated in hydrophilic shell that allows for aqueous solubility, and thus absorption into the blood.16, 17, 18  Another approach is the development of curcumin derivatives or molecular analogues, new molecules that have some of the same therapeutic biochemical effects on cancer pathogenesis, but have greater bioavailability due to their different molecular composition.14 Another method of increasing aqueous solubility of curcumin is to produce metal chelates of curcumin.14, 19  All of these strategies are subjects of current study.

Websites, glossy magazines and direct mail brochures are full of various claims about “super foods,” “natural remedies” and “miraculous” cures. Innumerable “dietary supplements” are available in stores and by mail to address ailments both real and imagined. It can be very difficult for the lay person to distinguish false claims and strong innuendo from effective substances which, for one reason or another, are not sold as drugs. This could be because the process of validating effectiveness and safety of new compounds can take more than ten years. It could also be because the testing process is usually very expensive, so that if there is no way to monetize some remedy, there may be no company or other research funder willing to make the necessary investment.

In this context, it seems medicines derived from turmeric are much more likely to follow the course set by willow bark and aspirin, rather than that set by the examples of Mesmerism or crystal healing. The chemical makeup of curcumin and its related compounds are known. Scientific evidence of its therapeutic effects goes back to the 1940s. The anticancer effects of curcumin have been demonstrated in vitro in many studies, and in vivo results are beginning to emerge. Further, researchers have not only given us positive outcomes, but have also identified the causal mechanisms for these effects. For those who suffer from cancer now, those who will tomorrow, and their loved ones, we can only hope that the bioavailability problems will be quickly solved, and that curcumin-based chemotherapies will fulfill the hopes of patients and medical providers around the world.

 

References

  1. Mohandas KM, DesaiDC: Epidemiology of digestive tract cancers in India. V. Large and small bowel. Indian J Gastroenterol 1999, 18:118-121. http://www.indianjgastro.com/IJG_pdf/july1999/118-121.pdf
  2. John D. Potter, Martha L. Slattery, Roberd M. Bostick, and Susan M. Gapstur, Colon Cancer: A Review of the Epidemiology. Epidemiol Rev (1993) 15 (2): 499-545.
  3. Subash C Gupta, Sridevi Patchva, Wonil Koh, and Bharat B Aggarwal, Discovery of Curcumin, a Component of the Golden Spice, and Its Miraculous Biological Activities, Clin Exp Pharmacol Physiol. 2012 March ; 39(3): 283–299. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288651/pdf/nihms-340487.pdf
  4. Center for Complementary and Alternative Medicine, Herbs at a Glance: Turmeric.  http://nccam.nih.gov/health/turmeric/ataglance.htm
  5. Subash C Gupta, Sridevi Patchva, Wonil Koh, and Bharat B Aggarwal, Discovery of Curcumin, a Component of the Golden Spice, and Its Miraculous Biological Activities, Clin Exp Pharmacol Physiol. 2012 March ; 39(3): 283–299. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288651/pdf/nihms-340487.pdf
  6. Aggarwal BB, Kumar A, Bharti AC., Anticancer potential of curcumin: preclinical and clinical studies., Anticancer Res. 2003 Jan-Feb;23(1A):363-98.  http://www.curcuminresearch.org/PDF/Anticancer%20potential.pdf
  7. Ramadasan Kuttan, P. Bhanumathy, K. Nirmala, M.C. George, Potential anticancer activity of turmeric (Curcuma longa), Cancer Letters, Volume 29, Issue 2, November 1985, Pages 197–202.
  8. Toshihiko Kawamori, Ronald Lubet, Vernon E. Steele, Gary J. Kelloff, Robert B. Kaskey, Chinthalapally V. Rao, and Bandaru S. Reddy, Chemopreventive Effect of Curcumin, a Naturally Occurring Anti-Inflammatory Agent, during the Promotion/Progression Stages of Colon Cancer, Cancer Res February 1, 1999 59; 597. http://cancerres.aacrjournals.org/content/59/3/597.long
  9. Prakobwong S, GuptaSC, Kim JH, Sung B, Pinlaor P, Hiraku Y, Wongkham S, Sripa B, Pinlaor S, Aggarwal BB. Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways. Carcinogenesis. 2011 Jul 20.               http://www.curcuminresearch.org/PDF/carcinogenesis-2011.pdf

10. Cheng, A. L.; Hsu, C. H.; Lin, J. K.; Hsu, M. M.; Ho, Y. F.; Shen, T. S.; Ko, J. Y.; Lin, J. T.; Lin, B. R.; Ming-Shiang, W; Yu, H. S.; Jee, S. H.; Chen, G. S.; Chen, T. M.; Chen, C. A.; Lai, M. K.; Pu, Y. S.; Pan, M. H.; Wang, Y. J.; Tsai, C. C.; Hsieh, C. Y. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001, 21 (4B), 2895–900.  http://www.ncbi.nlm.nih.gov/pubmed/11712783

11. GuptaSC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013 Jan;15(1):195-218.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535097/pdf/12248_2012_Article_9432.pdf

12. Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, Wexner SD, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006;4(8):1035–1038.  http://download.journals.elsevierhealth.com/pdfs/journals/1542-3565/PIIS1542356506002783.pdf

13. He ZY, Shi CB, Wen H, Li FL, Wang BL, Wang J. Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer Investig. 2011;29(3):208–213.  http://informahealthcare.com/doi/abs/10.3109/07357907.2010.550592

14. Anand, P., A. B. Kunnumakkara, et al. (2007). “Bioavailability of curcumin: problems and promises.” Mol Pharm 4(6): 807-18. http://www.curcuminresearch.org/PDF/Anand%20P-23.pdf

15. Curcumin therapeutic promises and bioavailability in colorectal cancer, Shehzad, A., Khan, S., Shehzad, O., Lee, Y.S. Drugs Today 2010, 46(7): 523.  http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=4&p_RefId=1509560&p_IsPs=N

16. Bhawana, Basniwal RK, Buttar HS, Jain VK, Jain N. Curcumin nanoparticles: preparation, characterization, and antimicrobial study, J Agric Food Chem. 2011 Mar 9;59(5):2056-61. http://www.ncbi.nlm.nih.gov/pubmed/21322563

17. Savita Bisht, Georg Feldmann, Sheetal Soni, Rajani Ravi, Collins Karikar, Amarnath, Maitra, and Anirban Maitra. Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy, Journal of Nanobiotechnology 2007, 5:3.                   http://www.jnanobiotechnology.com/content/5/1/3

18. Mukerjee A, Vishwanatha JK. Formulation, characterization and evaluation of curcumin-loaded PLGA nanospheres for cancer therapy. Anticancer Res. 2009 Oct;29(10):3867-75.  http://ar.iiarjournals.org/content/29/10/3867.full.pdf

Tripathi L, Kumar P, Singhai AK. Role of chelates in treatment of cancer. Indian J Cancer 2007;44:62-71. http://www.indianjcancer.com/text.asp?2007/44/2/62/35813

 

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