biostudies-literatureQian WNCATS NIH HHSNCI NIH HHSNIGMS NIH HHS4180-94https://www.ebi.ac.uk/biostudies/studies/S-EPMC4147315biostudies-literatureUnknown5(12)Overcoming platinum drug resistance represents a major clinical challenge in cancer treatment. We discovered a novel drug combination using cisplatin and a class of thioquinazolinone derivatives including mdivi-1 (mitochondrial division inhibitor-1), that induces synergistic apoptosis in platinum resistant tumor cells, including those from cisplatin-refractory endstage ovarian cancer patients. However, through study of the combination effect on Drp1 (the reported target of mdivi-1) knockout MEF cells and the functional analysis of mdivi-1 analogs, we revealed that the synergism between mdivi-1 and cisplatin is Drp1-independent. Mdivi-1 impairs DNA replication and its combination with cisplatin induces a synergistic increase of replication stress and DNA damage, causing a preferential upregOncotargetNovel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells.PMC4147315P50 CA121973P30 CA047904P30CA047904P50 CA097190P50CA121973R01 CA169291P50CA097190UL1 TR000005R01 GM096208Qian WLlambi FMcDermott LARoginskaya VStolz DBEdwards RPWang JVan Houten BGreen DRfalseNovel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells.Overcoming platinum drug resistance represents a major clinical challenge in cancer treatment. We discovered a novel drug combination using cisplatin and a class of thioquinazolinone derivatives including mdivi-1 (mitochondrial division inhibitor-1), that induces synergistic apoptosis in platinum resistant tumor cells, including those from cisplatin-refractory endstage ovarian cancer patients. However, through study of the combination effect on Drp1 (the reported target of mdivi-1) knockout MEF cells and the functional analysis of mdivi-1 analogs, we revealed that the synergism between mdivi-1 and cisplatin is Drp1-independent. Mdivi-1 impairs DNA replication and its combination with cisplatin induces a synergistic increase of replication stress and DNA damage, causing a preferential upreg2014-01-01T00:00:00Z2014 Jun2025-04-22T16:52:19.693Z2019-03-27T01:34:48ZS-EPMC41473152495270410.18632/oncotarget.1944