Abstract
e14634 Background: Metformin and vitamin D each has been shown to have anti-colon carcinogenic effects in pre-clinical and epidemiologic studies. We tested the potential synergistic effects of Metformin and vitamin D3 against colorectal neoplasia in a DMH-DSS induced colitis-associated colon neoplasia mouse model. Methods: We randomized 182 5-week old ICR male mice into 7 groups: 1) normal controls; 2) DMH controls; 3) DSS controls; 4) DMH + DSS controls; 5) vitamin D3 (3 dosage groups), 6) metformin (3 dosage groups), and 7) vitamin D3 + metformin (3 dosage combinations). After 20 weeks of treatment, the mice were sacrificed and colon tissues were harvested and examined for multiplicity of adenoma/cancer, volume of each tumor, number and score of aberrant crypt foci (ACF). Results: Compared to the DMH + DDS controls, combination of vitamin D3 (200 IU/kg/day) and metformin (240 mg/kg/day) statistically significantly reduced the average number of adenoma/cancer per mouse formed (6.20 ± 3.68 vs. 2.20 ± 2.12, p<0.01), volume (mm3 ) of tumor (115.46 ± 107.32 vs. 31.05 ± 38.26, p< 0.05), number of ACF (0.46 ± 0.88 vs. 2.58 ± 1.93, p <0.01), and ACF score (5.00 ± 3.26 vs. 1.23 ± 2.04, p <0.01). Western blot and IHC show that vitamin D3 potentiates metformin in activating AMPK (phos-AMPK: 0.53 ± 0.01 vs. 0.70 ± 0.03, p < 0.01), inhibiting AKT (phos-AKT: 0.39 ± 0.10 vs. 0.15 ± 0.04, p < 0.01), S6P (phos-S6P: 0.36 ± 0.03 vs. 0.14 ± 0.04, p <0.01), cyclin D1 (0.24 ± 0.02 vs. 0.06 ± 0.02, p <0.01), ?-catenin (0.808 ± 0.142 vs. 0.010 ± 0.001, p < 0.01), and VDR (0.182 ± 0.045 vs. 0.488 ± 0.081). Combination treatment also statistically significantly increases serum levels of IGFBP-3, with little effect on IGF-1, IGFBP-1 or IL-1?. Conclusions: Metformin and vitamin D3 synergistically inhibit the development of colorectal neoplasia in a colitis-associated mouse colon carcinogenesis model. Further study of the underlying mechanisms is warranted.
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