Valproic acid suppresses growth and enhances cisplatin cytotoxicity to larynx cancer cells

Introduction Larynx cancer is the most common head and neck neoplasia in developed nations. The treatment of advanced larynx cancer include chemotherapy, often using cisplatin. The limitations of many antineoplastic drugs are their low delivery into respiratory tissues, thus the need of higher doses which results in severe side effects, and the development of drug resistance by cancer cells. Therefore the need of drugs and drug combinations that potentiates each other, increasing safety by reducing doses and act on several pathways at the same time, acting more specifically on cancer cells. Histone deacetylase inhibitors are a promising new class of anticancer agents. Among them valproic acid is a well-established drug in psychiatry with a potential use in cancer treatment. Here we study the mechanisms of action of valproic acid on larynx cancer cells. Materials and methods Viability, proliferation and migration of laryngeal cancer cell lines (RK33 and RK45) were studied by methylthiazolyldiphenyl-tetrazolium bromide (MTT) method, 5-bromo-2deoxyuridine (BrdU) incorporation assay and the wound assay, respectively. Acetylation of histone H3 was detected by Western blotting. Flow cytometry was used to determine cell cycle progression. Apoptosis was assessed by means of nucleosomes released to cytosol and the genes expression by quantitative polymerase chain reaction (qPCR) method. Results Valproic acid treatment resulted in reduced proliferation and migration, increase in apoptosis, and cell cycle arrest in larynx cancer cells tested in our study. Valproic acid treatment induced the hyperacetylation of histone 3 K18 (H3 K18ac), resulting in de novo expression of CDKN1A and simultaneously repressing of CCND1, thus affecting cell cycle progression. Moreover, valproic acid significantly potentiates the antineoplastic activity of cisplatin on larynx cancer cells, at low doses by increasing apoptosis, cell cycle arrest and reduced migration. Conclusion Overall, our results suggest that valproic acid can potentially be used as a therapeutic agent against larynx tumours, but it can also be used in combination with current treatments of choice to enhance their efficiency on cancer cells while reducing side effects.