Mocetinostat as a novel selective histone deacetylase (HDAC) inhibitor in the promotion of apoptosis in glioblastoma cell line C6 and T98G

Abstract

Abstract Histon deacetylase (HDAC) enzyme is one of the enzymes involved in regulating gene expression and epigenetic alternation of cells by removing acetyl groups from lysine residue on a histone, allowing the histones to wrap the DNA more tightly and suppressing a tumor-suppressing gene. HDAC inhibitors play an important role in inhibiting the proliferation of tumor cells by restricting the mechanism of action of HDAC enzyme, leading to the addition of acetyl groups to lysine. Mocetinostat, also known by its chemical name (MGCD0103), is a novel isotype selective HDAC enzyme that explicitly targets HDAC isoforms inhibiting Class1(HDAC 1,2,3,8) and Class IV (HDAC11) enzymes. It was approved for treating the phase II trial of Hodgkin's lymphoma in 2010. Our study revealed that different doses of Mocetinostat inhibit the growth of glioblastoma cells, metastasis, and angiogenesis and induce the apoptosis and differentiation of glioblastoma cells C6 and T98G. Western blot has shown that MGCD0103 has many biological activities to control glioblastoma cancer cells. MGCD0103 can modulate the molecular mechanism for several pathways in cells, such as inhibition of the PI3K/AKT pathway and suppression of HDAC1 enzyme activity in charge of many biological processes in the initiation and progression of cancer. The high doses of Mocetinostat drug significantly induce apoptosis and suppress cancer cell proliferation through increased pro-apoptotic proteins (BAX) and a down level of anti-apoptotic proteins(Bid, Bcl2). Also, the mocetinostat upregulated the expression of the tumor suppressor gene and downregulated the gene expression of the E2f1 transcription factor. Additionally, MGCDO103-induced differentiation was facilitated by activating the differentiation marker GFAP and preventing the undifferentiation marker from expression (Id2, N-Myc). The MGCD0103 is a potent anticancer drug crucial in treating glioblastoma cells.