Combined Use of Vitamin D3 and Metformin Exhibits Synergistic Chemopreventive Effects on Colorectal Neoplasia in Rats and Mice

Abstract

Vitamin D3 and metformin are widely used in humans for regulating mineral metabolism and as an anti-diabetic drug respectively; and both of them have been shown to have chemopreventive effects against various tumors. This study was designed to investigate the potential synergistic chemopreventive effects of vitamin D3 and metformin against the development of early colon neoplasia in two models. The first model was a 1, 2-dimethylhydrazine dihydrochloride (DMH) induced colon cancer rat model and the second, a DMH-dextran sodium sulfate (DSS) induced colitis-associated colon neoplasia mouse model. Compared to either vitamin D3 or metformin alone, combined use of vitamin D3 and metformin showed more pronounced effect in reducing the numbers of aberrant crypt foci (ACF) and tumor in the colon. The most prominent inhibitory effects were observed in the vitamin D3 medium dose (100 IU/kg/day) and metformin medium dose (120 mg/kg/day) combination group. Furthermore, our results showed that enhancement of metformin’s chemopreventive effects by vitamin D3 was associated with down-regulation of S6P expression, via the AMPK (IGF-1)/mTOR pathway. In addition, and enhancement of vitamin D3’s chemopreventive effects by metformin was associated with inhibition of the protein expressions of c-Myc and Cyclin D1, via the vitamin D receptor/β-catenin pathway. These findings show that combined use of vitamin D3 and metformin exhibits synergistic effects against the development of early colon neoplasia. They suggest that the combined use of vitamin D3 and metformin may represent a novel strategy for chemoprevention of colorectal cancer.

Metformin prevents hormonal and metabolic disturbances and 1,2-dimethylhydrazine-induced colon carcinogenesis in non-diabetic rats

“…We observed increased levels of glucose, insulin, IGF-1, total cholesterol, triglycerides, MDA, glycated hemoglobin, and VEGF in serum of rats with DMH-induced colon tumors compared with the group without DMH ( Figure 1 ). These findings agree with available data 12,13,26,27 . Furthermore, we observed the normalizing effects of both MF doses on these parameters in DMH-exposed rats ( Figure 1 ).…”

“…Meanwhile, the anti-diabetic biguanide, metformin (MF), lowers elevated insulin levels in type 2 diabetes 3,9 , significantly reduces various cancer risks in humans with the condition, and prevents tumor development in numerous rodent tissues and organs 10,11 . Furthermore, MF inhibits some chemically induced colon carcinogenesis in diabetic, obese 12 , and non-diabetic rats 13 . In this work, we showed the inhibitory effects of MF on DMH-induced colon carcinogenesis in non-diabetic rats.…”

Differences in p53 status significantly influence the cellular response and cell survival to 1,25‐dihydroxyvitamin D3‐metformin cotreatment in colorectal cancer cells

“…8 In the case of metformin, p53 has been shown to impact cellular fate in response to treatment, as well as the elicited metabolic responses. 7 Several lines of evidence have illustrated that the combination of both molecules induces synergistic anti-cancer effects in different cancer models, including prostate, 13 breast, 14 as well as CRC, 15 however, the impact of p53 status on this treatment regimen is unknown. We employed three CRC cell lines with very distinct differences in p53 status-wt (HCT116), p53-null (HCT116 p53−/−), mutant p53 (R273H; HT-29 cells) -and performed extensive analysis of the effects of the combination on cellular proliferation, metabolism, as well as expression and/or activity of players involved in diverse signaling, namely Wnt/β-catenin, AMPK/ mTOR, and tyrosine kinase signaling.…”

Deciphering the molecular mechanism and apoptosis underlying the in‐vitro and in‐vivo chemotherapeutic efficacy of vanadium luteolin complex in colon cancer

“…The cell cycle phase distribution was determined by FACS analysis by ModFit software, and the histogram of DNA content against counts was displayed by a double labelling system of both FITC conjugated Annexin‐V and PI medium of complex treated at 5, 15, and 25 μM concentrations, respectively. Untreated cultured HT‐29 cells (1 × 10) were observed after 36 hours to distinguish between apoptosis and necrosis by flow cytometer using Cell Quest software …”