After stage, platinum drug resistance is the single most important factor in determining prognosis in ovarian cancer. Overcoming platinum drug resistance by pharmacological manipulations represents a major challenge in the current clinical practice for the management of ovarian cancer. We discovered a novel drug combination approach using platinum agents with mdivi-1 (mitochondrial division inhibitor 1) that is able to synergistically induce rapid apoptosis in platinum-resistant ovarian cancer cells, including established cisplatin-resistant ovarian cancer cell lines as well as primary cancer cells derived from ovarian cancer patients. We also identified that the synergism between cisplatin and mdivi-1 is not dependent on Drp1 (a mitochondrial fission protein and the reported target of mdivi-1), as mdivi-1 enhances cisplatin toxicity in Drp1 knockout mouse embryonic fibroblast (MEF) cells. In order to improve the compound properties of mdivi-1, we performed a structure activity relationship (SAR) study of mdivi-1 and assembled and screened a small library of structurally related compounds. We were able to identify more potent novel small molecules that synergize with platinum agents. We found that short-term exposure of cells to the combination of cisplatin and those novel compounds is sufficient to reduce cell viability, while cisplatin alone treatment only slightly inhibited cell proliferation in cisplatin-resistant ovarian cancer cells. We further identified that mdivi-1 and its structurally related novel small molecules, when combined with cisplatin, induce a synergistic increase of replication stress and DNA damage, causing upregulation of a pro-apoptotic Bcl-2 family protein Noxa. These small molecules also repress mitochondrial respiration and the combination with cisplatin triggers substantial mitochondrial dysfunction including mitochondrial uncoupling. DNA replication stress and mitochondrial dysfunction converge on the induction of mitochondrial outer membrane permeabilization (MOMP) proceeding robust mitochondrial apoptotic signaling, bypassing a Bax/Bak-dependent mechanism. Since apoptosis induced by cisplatin alone relies on Bax/Bak-dependent MOMP, and inefficient activation of Bax/Bak-dependent MOMP is often associated with cisplatin resistance, the combination of cisplatin and mdivi-1 family compounds represents a novel strategy in overcoming platinum resistance. We thus present a novel platinum-based combination approach in the treatment of platinum resistant ovarian cancer.
Citation Format: Wei Qian, Jingnan Wang, Robert Edwards, Peter Wipf, Bennett Van Houten. Novel small molecules overcoming platinum drug resistance in ovarian cancer cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1425.