Mo1167 Combination Therapy With Metformin and VSL#3 Attenuates Tumor Growth in Western-Style Diet Induced Colitic Cancer Model

Background: Western-style diet (WD) is known to be associated with insulin resistance and colonic inflammation which contributes to carcinogenesis. Biguanide metformin (M) and probiotics VSL#3 (V) can reduce insulin resistance and intestinal inflammation to inhibit tumor growth. We investigated the chemopreventive effect and the mechanism of the agents in WD-induced colitis associated carcinogenesis Methods: Male BALB/c mice were fed a control diet (CD) or WD for 8 weeks and WD groups were divided into groups of no treatment, M alone, V alone and combination therapy (CT). They were exposed to azoxymethane (AOM, 10mg/kg) and followed by 2 % dextran sodium sulfate (DSS) for 7 days. Tumor mass area was measured and tumor nodules were counted in colon of sacrificed mice. Disease activity index (DAI) was checked for 7 days during DSS exposure. Plasma glucose and insulin levels were measured and F4/80, Ki-67, claudin-1 and AMPK expressions were evaluated. Results: Tumor mass area and number of tumor nodules (.4 mm) were significantly decreased in CT group compared with WD group (p,0.01, p=0.016, respectively) and CT group showed low Ki-67 proliferation index (p,0.01). Plasma insulin and glucose levels in treatment groups (M, V, and CT group) were lower than those in WD group. CT group revealed low scores of DAI and decreased F4/80 positive cells accumulation during colitis compared with WD group (p=0.03, p,0.05, respectively). CT group showed maintained epithelial integrity by claudin-1 expression and increased AMPK activation. Conclusions: These results provide that combination therapy with metformin and VSL#3 attenuates tumor growth in WD induced colitic cancer model, which suggest that the treatment strategy could be useful in chemoprevention of colon cancer. The possible mechanisms were AMPK activation and inhibiting macrophage infiltration by maintaining epithelial integrity during colitis. Key word: colitic cancer, chemoprevention, metformin, VSL#3, western-style diet