title: Mitochondrial division inhibitor 1 (mdivi-1) enhances death receptor-mediated apoptosis in human ovarian cancer cells.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of a variety of cancers including ovarian cancer. However, the inherent or acquired resistance of tumor cells to TRAIL limits the potential application of TRAIL-mediated therapy. In this study, we identified that mitochondrial division inhibitor-1 (mdivi-1) is able to enhance the sensitivity of human ovarian cancer cells to death receptor ligands including TRAIL, FAS ligands, and TNF-α. Importantly, the combination of TRAIL and mdivi-1 has no apparent cytotoxic effect on non-transformed human cells, indicating a significant therapeutic window. We identified that caspase-8 and not the modulation of TRAIL receptors is required for the combination effect of TRAIL and mdivi-1. We further demonstrated that the enhanced efficacy of combination of mdivi-1 and death ligands is not dependent on the originally reported target of mdivi-1, Drp1, and is also not dependent on the two important pro-apoptotic Bcl-2 family proteins Bax and Bak. Thus, our study presents a novel strategy in enhancing the apoptotic effect of death receptor ligands and provides a new effective TRAIL-based combination approach for treating human ovarian cancer.
authors.affiliation: Tsinghua University School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Obstetrics & Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Karyn
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Department of Obstetrics & Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Edwards
authors.affiliation: Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh and Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. Electronic address: vanhoutenb@upmc.edu.
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.affiliation: Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh and Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. Electronic address: qianw@upmc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004354:Drug Screening Assays, Antitumor; D034281:Dynamins; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D052999:Quinazolinones / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; D008024:Ligands; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D052999:Quinazolinones; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C505530:CASP8 protein, human; D053181:Caspase 8; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Bax/Bak; Death ligands; Drp1; Ovarian cancer; TRAIL; mdivi-1