Abstract A57: Randomized double-blind trial of a rational combination of anthocyanins and curcumin for colon cancer prevention in subjects with colorectal adenomas: MIRACOL study

Abstract

Abstract Rationale: Colorectal cancer (CRC) is one of the most frequent malignant neoplasms in both sexes within developed countries. Colorectal carcinogenesis is a multistage process that occurs over a period of 10–20 years. Colorectal adenomas (CA) are well recognized CRC risk markers. Evidence from epidemiological studies and clinical trials, suggests that removal of CA decreases the incidence of CRC, supporting the hypothesis that regression or elimination of CA through chemopreventive strategies would also reduce CRC's incidence. Inflammation and oxidative stress appear to play a crucial role in the development of CRC; NF-kB activation has been associated with multiple pathways of oncogenesis, including apoptosis, cell cycle control, differentiation, angiogenesis and cell migration; interference with these mechanisms may represent a strategy in CRC chemoprevention. Anthocyanins and curcumin represent, so far, the two most reliable candidates mainly due to their integrated capacity of modulating key steps of inflammatory processes, cell proliferation and tumor progression. Anthocyanins are a group of natural occurring pigments responsible for the red-blue color of many fruits and vegetables and are provided with remarkable antiproliferative, apoptogenic, antiinflammatory and antioxidant effects and with the capacity of inhibiting tumor progression in experimental models of gastrointestinal cancerogenesis. In a recent pilot study in CRC patients, anthocyanins administered for 7 days were dose-dependently effective in reducing the proliferation index Ki-67. Curcumin is a polyphenolic compound obtained from turmeric (Curcuma longa L.) endowed with marked anti-inflammatory, antioxidant and antineoplastic effects; due to its peculiar proximal carbonyls, curcumin is also effective in interacting with the intracellular redox status contributing to modulate main steps of cellular activation and proliferation. In the present study, we propose to test a rational combination of a natural enriched source of anthocyanins from bilberry (Vaccinium myrtillus L.), MIRTOSELECT© (standardized to contain 36 % anthocyanins) with a bioavailable form of curcumin, MERIVA©. Based on previous experience in humans, the proposed daily dosages of 1g of MIRTOSELECT© and 1g of MERIVA© would assure an effective concentration of anthocyanins and curcumin in the target tissue; and at plasmatic level. Design: To assess the effects of MIRTOSELECT© and MERIVA© on cell proliferation in both adenomatous and unaffected colonic tissue, we designed a presurgical, double blind, placebo-controlled, randomized phase I/II trial in patients with colorectal adenomatous polyps. After a complete colonoscopy and biopsy of the index polyp, 100 subjects with histologically confirmed CA will be assigned (50 per arm) to either placebo or MIRTOSELECT© 1g/d + MERIVA© 1gr/die treatment for 4–6 weeks before polyp removal. Primary endpoint will be the nuclear transcriptional activation marker β-Catenin in adenoma tissue in subjects treated with the complex compared with placebo. The study is designed to have 85% power to detect an absolute difference of 10% between arms in β-Catenin expression levels in adenoma tissue after treatment, assuming 10% lost to follow-up. Secondary endpoints include treatment modulation of biomarkers of oxidative activation (NF-kB), proliferation and apoptosis (Ki67, TUNEL), phlogosis (u-CRP), circulating IGFs (IGF-1, IGFBP-3), genetic expression profile and tolerability. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A57.