Oncotarget

Research Papers:

Novel histone deacetylase inhibitor MPT0G009 induces cell apoptosis and synergistic anticancer activity with tumor necrosis factor-related apoptosis-inducing ligand against human hepatocellular carcinoma

Mei-Chuan Chen _, Hui-Hsuan Huang, Chin-Yu Lai, Yi-Jyun Lin, Jing-Ping Liou, Mei-Jung Lai, Yu-Hsuan Li, Che-Ming Teng and Chia-Ron Yang

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Oncotarget. 2016; 7:402-417. https://doi.org/10.18632/oncotarget.6352

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Abstract

Mei-Chuan Chen1,2,*, Hui-Hsuan Huang3,*, Chin-Yu Lai3, Yi-Jyun Lin4, Jing-Ping Liou5, Mei-Jung Lai6, Yu-Hsuan Li5, Che-Ming Teng3, Chia-Ron Yang4

1Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

3Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan

4School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan

5School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

6Center for Translational Medicine, Taipei Medical University, Taipei, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Chia-Ron Yang, e-mail: [email protected]

Keywords: HDAC, apoptosis, FLIP, TRAIL

Received: July 26, 2015     Accepted: October 26, 2015     Published: November 07, 2015

ABSTRACT

Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death; therefore, more effective anticancer therapies for the treatment of HCC are needed. Histone deacetylase (HDAC) inhibitors serve as promising anticancer drugs because they can induce cell growth arrest and apoptosis. We previously reported that 3-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N-hydroxyacrylamide (MPT0G009)—a novel 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines compound—demonstrated potent pan-HDAC inhibition and anti-inflammatory effects. In this study, we evaluated the anti-HCC activity of MPT0G009 in vitro and in vivo. Growth inhibition, apoptosis, and inhibited HDAC activity induced by MPT0G009 were more potent than a marketed HDAC inhibitor SAHA (Vorinostat). Furthermore, MPT0G009-induced apoptosis of Hep3B cells was characterized by an increase in apoptotic (sub-G1) population, loss of mitochondrial membrane potential, activation of caspase cascade, increased levels of pro-apoptotic protein (Bim), and decreased levels of anti-apoptotic proteins (Bcl-2, Bcl-xL, and FLICE-inhibitory protein); the downregulation FLIP by MPT0G009 is mediated through proteasome-mediated degradation and transcriptional suppression. In addition, combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with lower concentrations (0.1 μM) of MPT0G009 were synergistic in cell growth inhibition and apoptosis in HCC cells. In the in vivo model, MPT0G009 markedly reduced Hep3B xenograft tumor volume, inhibited HDAC activities, and induced apoptosis in the Hep3B xenografts. Our results demonstrate that MPT0G009 is a potential new candidate drug for HCC therapy.


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