title: Sensitization of hepatocellular carcinoma cells to Apo2L/TRAIL by a novel Akt/NF-κB signalling inhibitor.
abstract: Hepatocellular carcinoma (HCC) cells are intrinsically resistant to tumour necrosis factor-related apoptosis ligand (Apo2L/TRAIL), in part, due to the compensatory activation of nuclear factor-kappaB (NF-κB). To broaden the clinical utilization of Apo2L/TRAIL in HCC, OSU-A9, a potent indole-3-carbinol-derived Akt/NF-κB signalling inhibitor was used to overcome the intrinsic resistance. The antitumour effects of OSU-A9, Apo2L/TRAIL and the therapeutic combination were assessed by MTT assay, caspase activation and PARP cleavage, and the synergistic interactions were determined by Calcusyn analysis. NF-κB reporter gene and RT-PCR were tested for the activation of NF-κB and the expression of death receptors (DR)4 and 5. OSU-A9 could sensitize HCC cells to Apo2L/TRAIL with high potency through down-regulation of Akt/NF-κB signalling. OSU-A9 dose-dependently reduced Akt phosphorylation and the expression and nuclear localization of RelA/p65, accompanied by parallel decreases in the expression of NF-κB target products, including Bcl-xL, Mcl-1, cIAP1, cIAP2 and survivin. Moreover, OSU-A9 increased DR5 expression through a reactive oxygen species (ROS)-dependent mechanism. Concertedly, these mechanisms underlie the synergistic interaction between OSU-A9 and Apo2L/TRAIL in mediating apoptotic death in HCC cells. The ability of OSU-A9 to accentuate Apo2L/TRAIL-induced apoptosis by inactivating Akt/NF-κB signalling might foster a promising therapeutic strategy for HCC.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; Department of Pharmacology, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
authors.forename: Hany A
authors.initials: HA
authors.lastname: Omar
authors.forename: El-Shaimaa A
authors.initials: el-SA
authors.lastname: Arafa
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Maghrabi
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000432:Methanol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000502:physiology
chemical_list: C523234:(1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl)-methanol; D007211:Indoles; D016328:NF-kappa B; C498143:RELA protein, human; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051996:Transcription Factor RelA; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053181:Caspase 8; D000432:Methanol