Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Cancer is a multifactorial disease and its treatment requires combining different drugs to act synergistically. Epigenetic factors play a key role in cancer etiology and drug response. Modification of these epigenetic changes is a promising avenue for the development of new and effective therapies. 5-Fluorouracil (5-FU), an anti-metabolite, is the gold standard in treatment of colorectal cancer and valproic acid (VPA) is a histone deacetylase inhibitor, thus it has an epigenetic modifying effect. The aim of the current study was to investigate the epigenetic modifying effect of valproic acid (VPA) on 5-florouracil (5-FU) cytotoxic effect in CRC cell lines (Caco2 and HCT 116) and explore the possible underlying mechanism(s) of their interaction. Different combination regimens of 5-FU and VPA were analyzed using the factorial design. The maximum inhibitory combinations, as well as the minimum inhibitory combinations, were chosen to study the differential effect of VPA on various epigenetic markers as global DNA methylation ratio, histone acetyl transferase (HAT) activity and histone 3 (H3) acetylation percentage. Moreover, different metastatic parameters were studied as vascular endothelial growth factor level, matrix metalloproteinases (MMPs) activity and SNAI1 protein expression. Apoptosis was assessed by measuring Caspase-3 level, Caspase-9, ITPK1, AKT and Bcl-2 protein expression. Also, thymidine synthetase (TS) level was determined in cell culture medium

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