Reviewed: Carroll RE, Benya RV, Turgeon DK, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). 2011;4(3):354-364.
Curcumin is a biologically active compound derived from turmeric (Curcuma longa, Zingiberaceae) root and has anti-inflammatory, antioxidant, and antineoplastic activity (preventing the growth of benign or malignant cancerous cells). The effects of curcumin on colorectal abnormal tissue development (called crypt foci) in humans have not been previously reported. Tobacco smokers develop more aberrant crypt foci—tube-like structures in the colon and rectum that are the precursors to polyps and colon cancer. The authors of this trial hypothesize that if curcumin could reduce the concentration of the eicosanoids prostaglandin E2 (PGE2) and 5-hydroxyeicosatetraenoic acid (5-HETE) in the colorectal lining, it could reduce the formation of aberrant crypt foci. The purpose of this phase IIa cancer prevention study was to measure the effects of oral curcumin on PGE2 and 5-HETE concentrations within aberrant crypt foci and on the number of aberrant crypt foci and their proliferation in an open-label, non-randomized study.
Participants were recruited from the University of Illinois at Chicago and the Colorectal Screening Clinic at the University of Michigan, Ann Arbor, Michigan. Eligible subjects were men or women who were currently smokers, aged 40 years or more, with a history of more than 3 pack-years (a participant who smoked at least 1 pack of cigarettes per day for 3 years), and 8 or more rectal aberrant crypt foci observed via magnification chromoendoscopy (colonoscopy). Excluded subjects were those who used nonsteroidal anti-inflammatory drugs for more than 10 days per month, unless they completed a 30-day washout period, or had a history of chronic inflammatory bowel disease, prior pelvic irradiation, or an endoscopically confirmed peptic ulcer within the previous 5 years. Subjects were treated for 30 days with 2 g/day (n=22) or 4 g/day (n=19) curcumin (micronized and provided by the National Cancer Institute’s Division of Cancer Prevention; Bethesda, Maryland). Biopsies of aberrant crypt foci and normal rectal mucosa were taken at baseline and post-treatment; and PGE2 and 5-HETE were measured, and crypt cell proliferation was evaluated. Blood was drawn to assess plasma curcumin levels. A post-treatment endoscopic examination was performed between day 30 and day 35, and curcumin was continued until the day of the exam to ensure that biopsies were obtained less than 4 hours postdose. All laboratory assessments were evaluated blindly. Treatment adherence was measured via phone call, patient diary, and pill count.
Both doses of curcumin did not significantly change PGE2 or 5-HETE concentrations between baseline and post-treatment in the normal mucosa or mucosa with aberrant crypt foci. The 2 g dose of curcumin did not alter the number of aberrant crypt foci between baseline and post-treatment. In contrast, however, the 4 g dose of curcumin significantly decreased the number of rectal aberrant crypt foci by 40% from baseline to post-treatment (17.8 vs. 11.1 foci, P<0.005). However, there was no corresponding decrease in Ki-67-detected mucosal proliferation. Only low levels of curcumin and its conjugates were detected in rectal mucosal biopsies. After treatment with 4 g of curcumin (but not 2 g curcumin), plasma levels of curcumin conjugate concentrations were significantly elevated (P=0.009). Both doses of curcumin were well tolerated. The most frequently reported adverse events were gastrointestinal disturbances (diarrhea, distention, and reflux).
The authors conclude that the 4 g dose of curcumin significantly reduced aberrant crypt foci formation, which is an important anticarcinogenic effect. The mechanism remains undetermined. The curcumin-induced reduction in aberrant crypt foci occurred via a systemic rather than a local effect. It is interesting that the anticarcinogenic activity occurred at the target tissue despite the lack of curcumin detected in the target tissue.
It should be noted that the subjects had to take 16 curcumin capsules/day to attain a 4 g dose. It is well known that patient compliance is low when numerous capsules have to be consumed. Therefore, it is possible that for this to be a viable anticancer option, the product should either be more concentrated (a difficult task with a pure compound like curcumin) or possibly made larger (i.e., if the increase does not create a difficulty in swallowing), so that fewer capsules would be required for daily consumption.
—Heather S. Oliff, PhD
Editor’s note: Blood plasma levels of curcumin are probably not highly important for colon cancer prevention since the curcumin and related compounds act in the intestinal mucosa and are not required to be in systemic circulation. For other types of tumors in other locations such systemic circulation certainly would be necessary. Some recently introduced commercial curcumin formulations are showing enhanced bioavailability. A peer reviewer of this trial review noted that researchers looked only at rectal biopsies—presumably due to their proximal access, raising the question as to whether curcumin may be more active in the upper areas of the colon.