A novel histone deacetylase (HDAC) inhibitor MHY219 induces apoptosis via up-regulation of androgen receptor expression in human prostate cancer cells.

Abstract

Histone deacetylase (HDAC) inhibitors are a new class of anticancer agents that act by inhibiting cancer cell proliferation and inducing apoptosis in various cancer cell lines. To investigate the anticancer effect of a novel histone deacetylase (HDAC) inhibitor MHY219, its efficacy was compared to that of suberoylanilide hydroxamic acid (SAHA) in human prostate cancer cells. The anticancer effects of MHY219 on cell viability, HDAC enzyme activity, cell cycle regulation, apoptosis and other biological assays were performed. MHY219 was shown to enhance the cytotoxicity on DU145 cells (IC₅₀, 0.36 μM) when compared with LNCaP (IC₅₀, 0.97 μM) and PC3 cells (IC₅₀, 5.12 μM). MHY219 showed a potent inhibition of total HDAC activity when compared with SAHA. MHY219 increased histone H3 hyperacetylation and reduced the expression of class I HDACs (1, 2 and 3) in prostate cancer cells. MHY219 effectively increased the sub-G1 fraction of cells through p21 and p27 dependent pathways in DU145 cells. MHY219 significantly induced a G2/M phase arrest in DU145 and PC3 cells and arrested the cell cycle at G0/G1 phase in LNCaP cells. Furthermore, MHY219 effectively increased apoptosis in DU145 and LNCaP cells, but not PC3 cells, according to Annexin V/PI staining and Western blot analysis. These results indicate that MHY219 is a potent HDAC inhibitor that targets regulating multiple aspects of cancer cell death and might have preclinical value in human prostate cancer chemotherapy, warranting further investigation.

• Authors: Nabanita Patra, Umasankar De, Tae Hyung Kim, Young Ju Lee, Mee Young Ahn, Nam Deuk Kim, Jung Hyun Yoon, Wahn Soo Choi, Hyung Ryong Moon, Byung Mu Lee, Hyung Sik Kim
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 67 Issue 5 Pg. 407-15 (Jun 2013) ISSN: 1950-6007 [Electronic] France
• PMID: 23583193 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• N1-hydroxy-N8-(4-(phenylamino)phenyl)octanediamide
• Receptors, Androgen
• Cyclin-Dependent Kinase Inhibitor p27
• Vorinostat
• Diphenylamine

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Diphenylamine (administration & dosage, analogs & derivatives, pharmacology)
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Humans
• Hydroxamic Acids (administration & dosage, pharmacology)
• Inhibitory Concentration 50
• Male
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Receptors, Androgen (genetics)
• Up-Regulation (drug effects)
• Vorinostat