Metformin Prevents DMH-induced Colorectal Cancer in Diabetic Rats by Reversing the Warburg Effect

Cancer Med. 2015 Nov;4(11):1730-41. doi: 10.1002/cam4.521. Epub 2015 Sep 17.

Abstract

Epidemiologic studies have shown that the treatment of diabetics with metformin reduced the risk of cancer-related mortality. Here, we investigated the chemopreventive effects of metformin on dimethylhydrazine (DMH)-induced colorectal carcinogenesis in diabetic SD rats following metformin treatment and the effect on Warburg effect involved in this process. Diabetic rat models were induced with high-fat feeding in combination with a low dose of Streptozotocin (STZ) and then induce colorectal cancer with a low dose of DMH. The formation of colorectal Aberrant crypt foci (ACF) and the incidence, number and size of the tumor were measured. The proliferation indices of colonic tissues were determined through Proliferating cell nuclear antigen (PCNA) immunostaining. Then detect the expression of PK and IDH in colonic tissues using immunohistochemistry and Western blot. The enzyme activities of HK and PDH in colonic tissues were measured. The growth and expression of PK and IDH and activity of HK and PDH in cell lines LoVo and HT-29 were measured after metformin treatment. The results showed that metformin treatment significantly inhibited the formation of ACF and tumors. The proliferation index of colonic tissues was significantly decreased following metformin treatment. In addition, metformin inhibited cell growth and decreased the imbalance in the expression of the enzymes involved in glycolysis and the TCA cycle. These findings suggested that metformin might produce a synergistic colon cancer-preventative effect in diabetic patients through the regulation of the enzymes expression involved in glucose metabolism.

Keywords: Colorectal cancer; diabetes mellitus; glucose metabolism; metformin; warburg effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / drug therapy
  • Disease Models, Animal
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Metformin / pharmacology*
  • Rats
  • Tumor Burden

Substances

  • Biomarkers
  • Metformin