Institute of Pharmacy, Nirma University, Ahmedabad 382 481, India.
Eur J Pharm Sci. 2018 Aug 30;121:188-199. doi: 10.1016/j.ejps.2018.05.026. Epub 2018 May 28.
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.
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.
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. IC 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.
Sodium valproate can be considered for repurposing in colon cancer associated with diabetes mellitus.
糖尿病患者患结肠癌的风险更高。组蛋白去乙酰化酶（HDACs）是两者的共同作用靶点。本研究的主要目的是评估丙戊酸钠对 2 型糖尿病相关结肠癌的影响。
使用高脂肪饮食和链脲佐菌素诱导 2 型糖尿病。在确认糖尿病后，从第 7 周到第 20 周，每周一次用 1,2 二甲基肼（25mg/kg，皮下注射）诱导结肠癌。从第 20 周到第 24 周给予丙戊酸钠（200mg/kg）治疗。在 24 周结束时，评估了几种酶和生化参数。在 HCT-15 细胞系中进行了 MTT、集落形成和划痕愈合试验。
疾病对照组动物出现高血糖、高胰岛素血症、细胞因子（TNF-α和 IL-1β）和癌胚抗原增加以及增殖细胞，丙戊酸钠治疗可预防这些变化。在疾病对照组动物中发现相对 HDAC2 mRNA 水平表达增加，丙戊酸钠治疗可降低其水平。丙戊酸钠对 HCT-15 细胞系的 IC50 在 48 小时和 72 小时分别为 3.40mM 和 3.73mM。丙戊酸钠还可剂量依赖性地防止集落形成和细胞迁移。
丙戊酸钠可考虑用于治疗与糖尿病相关的结肠癌。
