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 upregulation of a BH3-only
protein Noxa.
Mdivi-1 also represses mitochondrial respiration independent of Drp1, and the combination of
mdivi-1 and
cisplatin triggers substantial mitochondrial uncoupling and swelling. Upregulation of Noxa and simultaneous mitochondrial swelling causes synergistic induction of mitochondrial outer membrane permeabilization (MOMP), proceeding robust mitochondrial apoptotic signaling independent of Bax/Bak. Thus, the novel mode of MOMP induction by the combination through the "dual-targeting" potential of
mdivi-1 on DNA replication and mitochondrial respiration suggests a novel class of compounds for
platinum-based combination option in the treatment of
platinum as well as multidrug resistant
tumors.