Phase IIa clinical trial of Curcumin for the prevention of colorectal neoplasia.
Cancer Prev Res. 011; 4(3):354-64.
Curcumin has been shown to prevent aberrant crypt foci (ACF) and adenomas. It also inhibits production of procarcinogenic eicosanoids prostaglandin E2 (PGE2) and 5-hydroxyeicosatetraenoic acid (5-HETE) via inhibiting COX-1, COX-2 and 5-Lipoxigenase (5-LOX). Presence of ACF has been seen in rectum of smokers, which increases with years of tobacco use. Based on above findings it was speculated that by reducing concentration of PGE2 and 5-HETE in flat mucosa of colorectum, Curcumin would reduce colorectal epithelial crypt proliferation and ACF formation in current smokers.
To assess effect of oral administration of Curcumin (a major component of Curcumin C3 Complex®) on PGE2 within ACF, 5-HETE, ACF number and proliferation.
A non-randomized open-label phase IIa clinical trial, with 44 eligible smokers having eight or more ACF on screening colonoscopy, for 30 days was planned. The prevention trial had two stages: first with 2 g/day Curcumin and second with 4 g/day Curcumin. Pre and post treatment concentrations of PGE2 and 5-HETE in ACF and normal tissue biopsies by LCMS; ACF number via rectal endoscopy; proliferation by Ki-67 immunohistochemistry; and Curcumin concentration by HPLC in serum and rectal mucosa samples were assessed. Primary endpoint was reduction of concentration of PGE2 and 5-HETE within ACF and in associated normal mucosa and secondary endpoint included total ACF number and an estimate of proliferation in normal mucosa using the proliferation marker Ki-67.
- Forty-one patients completed the trial and were included in final toxicity and biomarker analysis.
- There was no significant change in the PGE2 concentrations of 2-g or 4-g cohort between baseline and post intervention.
- Curcumin supplementation did not reduce 5-HETE concentrations in ACF or normal mucosa of the 2-g or 4-g cohort.
- The number of rectal ACF in 2-g cohort did not change, however, it decreased significantly (40 %) in 4-g cohort (P<0.005)
- Post intervention Curcumin conjugate concentrations in plasma rose significantly (P=0.009) during treatment in the 4-g cohort.
- Curcumin was well tolerated by the patients at both 2 g/day dose and 4 g/day dose.
The study demonstrates that a short duration of Curcumin (a major component of Curcumin C3 Complex®) treatment reduces ACF number in humans, which is in accordance with the preclinical data available. The mechanism by which it happens remain unanswered. However, treatment related increase in conjugate concentrations in plasma suggests that ACF reduction resulted from systemic rather than local delivery of conjugates. These data verify that despite low bioavailability of Curcumin, anticarcinogenic activity occurs in tissue target. However, larger trials are needed in high-risk adenoma population, also the mechanism by which Curcumin reduces ACF needs to be identified to further support the use of Curcumin as cancer prevention agent.