Repurposing of sodium valproate in colon cancer associated with diabetes mellitus: Role of HDAC inhibition

Abstract

Background and purpose: Diabetic patients are at greater risk for colon cancer. Histone deacetylases (HDACs) serve as common target for both. The key objective of the study was to evaluate the effect of sodium valproate in type 2 diabetes mellitus associated colon cancer.

Experimental approach: High fat diet and streptozotocin were used to induce type 2 diabetes. Following this, after diabetes confirmation, colon cancer was induced using 1,2 dimethylhydrazine (25 mg/kg, s.c.) once weekly from 7th week to 20th weeks. Sodium valproate (200 mg/kg) treatment was given from 20th to 24th week. At the end of 24 weeks, several enzymatic and biochemical parameters, were estimated. MTT, clonogenic and scratch wound healing assay were carried out in HCT-15 cell line.

Key results: Hyperglycemia, hyperinsulinemia, increase in cytokines (TNF-α and IL-1β) and carcinoembryonic antigen and presence of proliferating cells was seen in disease control animals which was prevented by sodium valproate treatment. Overexpression of relative HDAC2 mRNA levels was found in diseased control animals, which was reduced by sodium valproate treatment. IC₅₀ of sodium valproate was found to be 3.40 mM and 3.73 mM at 48 h and 72 h respectively on HCT-15 cell line. Sodium valproate also dose dependently prevented colony formation and cell migration.

Conclusion and implications: Sodium valproate can be considered for repurposing in colon cancer associated with diabetes mellitus.

Keywords: 1,2 dimethylhydrazine (DMH); Clonogenic assay; HDAC2 mRNA; Ki-67; Scratch wound healing assay; Streptozotocin (STZ).