Proliferation and cellular death of A375 cell line in the presence of HDACs inhibitors.

Dynamic increase of a skin malignant melanoma (melanoma malignum) morbidity rate is observed in the world for several years. Though, this type of carcinoma comprises just 5% of all malignant skin cancers, it is responsible for a 75ñ80% of deaths caused by these tumors (1). Melanoma malignum is a cancer formed as a result of malignant transformation of melanin synthesizing cells ñ melanocytes. It can develop from moles or de novo in a normal skin. Over 90% of all melanoma cases occur in a skin, whereas in an eyeball, brain meninges, mucous membrane of oral cavity and genitalia it is more rarely observed (about 10%). For 50 years, progressive increase in melanoma incidence in the Western world is observed. The high grade of malignancy of that neoplasm is associated with rapid proliferation, numerous early metastases and high resistance to conventional treatment. Therefore, there is a demand for development of alternative antimelanoma therapies (2ñ4). Inhibitors of histone deacetylases (HDACs) are a group of compounds displaying clear anticancer activity (5, 6). They have been shown to inhibit proliferation, induce apoptosis and augment differentiation in a variety of tumor cells in vitro. Valproic acid (VPA, 2-propylpentanoic acid), a well known antiepileptic drug, has been shown to inhibit HDACs in some transformed cell lines. Several studies confirmed the influence of VPA on proliferation, apoptosis and differentiation processes in malignant cells. Besides, its antitumor properties include the inhibition of angiogenesis and metastasis. In melanoma cells, VPA induced the cell cycle arrest in G1 phase as well as apoptosis. This effect was associated with up-regulation of P16 protein ñ a cell cycle inhibitor. Generally, VPA is considered as a candidate drug useful both in the chemotherapy of advanced neoplasias and chemoprevention or control of residual minimal disease. Clinical trials included phase I/II study of the therapy with VPA combined standard chemoimmunotherapy of patients suffering from advanced stage melanoma (7, 8). Butyric acid, a four-carbon fatty acid, is a well known inhibitor of histone deacetylases. It is formed in the human colon as a result of anaerobic bacterial fermentation of dietary fiber. It is believed that butyrate plays an important chemopreventive role in colorectal carcinogenesis (9). The aim of our study was to compare the influence of sodium valproate (NaVP) and sodium butyrate (NaB) on morphology, growth rate and apoptosis in human melanoma cell line A375.