Anti-tumor Activity Of A Novel Histone Deacetylase Inhibitor,HDAC3

Histone deacetylases(HDAC)plays a major role in the remodeling of chromatin by the deacetylation process of the lysine residues that are presented on histone tails or other important proteins and receptors.It has been proved that HDAC is over-expressed in many neoplastic carcinomas such as lymphoma,leukemia,prostate cancer,gastric cancer,breast cancer,and colon cancer.The inhibition of the overactive HDAC enzymes has emerged as an important therapeutic target to combat the growth of various cancers.Several mechanisms have been proposed toward the function of HDAC inhibitors such as the arrest of cell growth and/or stimulation of cells differentiation,apotosis,and etc.Now,five HDAC inhibitors have been approved for the treatment of malignancies.Otherwise,dozens of compounds targeting HDAC are currently in clinical development against various solid tumors and hematopoietic malignances.HDAC3 was a novel,orally bioavailable small molecular histone deacetylase inhibitor.We elucidated the effect of HDAC3 on cancer cells porliferation in vitro at first.Cell viability was determined using CCK-8 kit.HDAC3 exhibited potent cytotoxicity against a panel of human cancer cell lines,including 5 lymphoma cell lines,1 leukemia cell line,and 3 solid tumor cell lines,with IC50 values ranging from 0.14-1.62 μM,which was comparable with SAHA.Moreover the mechanism of HDAC3-induced canner cells apotosis,in a concentration-and time-dependent manner,which was indicated by flow cytometric analysis using Annexin V-FITC / PI double staining.After treatment with 3 or 10 μM HDAC3 for 24 h,approximately 58.8% or 66.9% of Ramos cells underwent apoptosis.To further determine HDAC3’s effect on histone deacetylase enzyme inhibition at the cellular level,we did the western blot analysis.The results showed that HDAC3 significantly increased α-tubulin and H3 acetylation in Ramos and HCT-116 cells.We further investigated the compound’s antitumor activity in vivo in human lymphoma and colon cancer xenograft models.Mice were orally administered HDAC3 with 50,100,200 mg/kg·bid for two or three weeks.And dose-dependent tumor growth inhibition was exhibited in both models.In summary,we have identified that HDAC3,as an oral histone deacetylase inhibitor displays significant anti-tumor activity in vitro and in vivo.These data provide a significant rational for clinical trial of HDAC3.