Objective:High and growing statistics of cancer related death worldwide, which is due to the low efficiency of current therapeutic strategies, has made it crucial to search for novel approaches against resistant and metastatic malignant cells. Valproic Acid (VPA) is a class I histone deacetylase inhibitor with anticancer activities, as it induces cell cycle arrest, differentiation and apoptosis, and also synergistically enhances the activity of anticancer agents.In present study, we investigated VPA effects on the toxicity of chemotherapy drugs, cisplatin, paclitaxel and 5-fluorouracil, using esophageal cancer cells(KYSE30 cell line). Materials and Methods: To determine the half maximal inhibitory concentration (IC50) of VPA, HFF3 cells, human normal fibroblasts, and KYSE30 cells were treated with 5, 10, 20 and 40 mM VPA and viability of cells was evaluated by MTT assay 24, 48 and 72 h after treatment. Then, KYSE30 cells were treated with combinations of VPA + cisplatin, paclitaxel or 5-fluorouracil, in concentrations close and less than their IC50 values, for 4 consequence days. Finally, induced apoptosis was assessed by flow cytometry and FITC annexin V apoptosis detection kit with propidium iodide. Results: Upon VPA treatment and assessment of cell viability, the IC50 of VPA was determined >10 mM in both cell lines. Accordingly, KYSE30 cells were treated with various combining concentrations, including 1.25, 2.5 and 5 mM VPA + 1, 2 and 4 μg/ml cisplatin, 1, 2 and 4 μg/ml paclitaxel or 2.5, 5 and 10 μg/ml 5- fluorouracil. Current results revealed that 72 h after treatments, 5 mM VPA increased the toxicity of 1 μg/ml cisplatin, 1 μg/ml paclitaxel and 2.5 μg/ml 5-fluorouracil up to 21%, 15% and 12%, respectively. Moreover, flow cytometry analysisrevealed that combination of VPA + 5-fluorouracilincreased apoptosis up to 15.5%. Conclusion: Since cancer cells show innate or acquired resistance to conventional chemotherapy, it is necessary to design more effectivetherapeuticstrategies. Our results indicated that non-toxic concentration of VPA has synergic effects on cisplatin, paclitaxel and 5-fluorouracil. Therefore, VPA could be used in future studies to see if it has same effects on other drugs or act similarly in vivo.

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