Abstract
The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 +/- 6.45 before treatment versus 5.11 +/- 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 +/- 6.65 versus 7.56 +/- 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer.
Highlights
Colorectal cancer (CRC) is a major neoplasm worldwide [1], and its prevalence and mortality have been increasing [2]
We showed that metformin suppressed the azoxymethaneinduced formation of colorectal aberrant crypt foci (ACF) by activating AMPK [17]
The present study clearly shows that metformin suppressed the formation of human colorectal ACF
Summary
Colorectal cancer (CRC) is a major neoplasm worldwide [1], and its prevalence and mortality have been increasing [2]. A paradigm shift from surveillance for early detection of cancer or adenomas (polypectomy) to new preventive strategies, including chemoprevention, is needed to lower the burden of this disease. Several large epidemiologic and/or clinical studies have evaluated the possible effects of more than 200 agents, including fiber, calcium, and nonsteroidal anti-inflammatory drugs including aspirin and selective cyclooxygenase-2 (COX-2) inhibitors, in pro-. Nonsteroidal antiinflammatory drugs, especially COX-2 inhibitors alone or in combination, have shown the most promise for CRC risk reduction [4], but reports have revealed an increased risk of serious cardiovascular events associated with COX-2 inhibitor use [5, 6]. In light of the adverse cardiovascular effects of otherwise effective COX-2 inhibitors and ineffective clinical results with other agents that had shown promise in this setting, novel drugs that would be both safe and effective are needed for CRC prevention. CRC is associated with lifestyle-related diseases such as diabetes and obesity [7,8,9,10], and these conditions might represent new targets for CRC chemoprevention
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