Novel histone deacetylase inhibitor MPT0G009 induces cell apoptosis and synergistic anticancer activity with tumor necrosis factor-related apoptosis-inducing ligand against human hepatocellular carcinoma
Journal
Oncotarget
Journal Volume
7
Journal Issue
1
Pages
402-417
Date Issued
2016
Author(s)
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. ? 2015. Oncotarget.
Subjects
Apoptosis; FLIP; HDAC; TRAIL
SDGs
Other Subjects
3 [1 (4 methoxybenzenesulfonyl) 2,3 dihydro 1h indol 5 yl] n hydroxyacrylamide; BIM protein; caspase; FLICE inhibitory protein; histone deacetylase; histone deacetylase inhibitor; indole derivative; mpt 0 g009; proteasome; protein bcl 2; protein bcl xl; tumor necrosis factor related apoptosis inducing ligand; unclassified drug; vorinostat; 3-(1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide; apoptosis regulatory protein; FLICE inhibitory protein; histone; histone deacetylase; histone deacetylase inhibitor; hydroxamic acid; sulfonamide; tumor necrosis factor related apoptosis inducing ligand; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; Article; cancer inhibition; cell cycle G1 phase; concentration response; controlled study; down regulation; drug potency; drug potentiation; enzyme activation; enzyme inhibition; Hep3B cell line; hepatocellular carcinoma cell line; human; human cell; in vitro study; in vivo study; liver cell carcinoma; male; mitochondrial membrane potential; mouse; nonhuman; protein degradation; transcription regulation; tumor xenograft; animal; apoptosis; Carcinoma, Hepatocellular; cell line; drug effects; drug screening; gene expression regulation; genetics; Hep-G2 cell line; Liver Neoplasms; metabolism; nude mouse; reverse transcription polymerase chain reaction; tumor cell line; tumor volume; Western blotting; Animals; Apoptosis; Apoptosis Regulatory Proteins; Blotting, Western; Carcinoma, Hepatocellular; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line; Cell Line, Tumor; Drug Synergism; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Liver Neoplasms; Male; Mice, Nude; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides; TNF-Related Apoptosis-Inducing Ligand; Tumor Burden; Xenograft Model Antitumor Assays
Type
journal article