Mitochondria play a multifaceted role in tumorigenesis through regulation of energy production, biomass, redox state, and engagement of cell death pathways. The mitochondrial Q (coenzyme Q10)-pool facilitates electron transport from Complexes I and II to III and is essential for regulating these activities. Therefore, altering mitochondrial Q-pool homeostasis represents a potential therapeutic strategy in cancer. BPM 31510 is a Coenzyme Q10 containing lipid nanodispersion currently in clinical trials for pancreatic cancer. Here, we used BPM 31510 to assess how modulation of mitochondrial Q-pool homeostasis impacts mitochondrial electron transport chain function to activate regulated cell death. Pancreatic cancer cell lines (MIA PaCa-2 and Panc-1) represent models with sensitivity to BPM 31510 both in vitro and in vivo. Treatment with BPM 31510 (EC50 dose, 24 h) resulted in significant mitochondrial enrichment of CoQ10 compared to other subcellular compartments, and quantitatively, CoQ10 levels were 100 times higher in mitochondria isolated from BPM 31510 treated cells over untreated controls (MIA PaCa-2 untreated, 0.31 nmol/mg; treated, 39.4 nmol/mg; Panc1 untreated, 0.21 nmol/mg; treated, 29.3 nmol/mg). Alterations in mitochondrial respiration characterized by dose-dependent decreases in succinate- or glycerol-3-phosphate-fueled respiration were observed in cells treated with BPM 31510, while pyruvate or TMPD/ascorbate-fueled respiration was only modestly affected, suggesting that BPM31510 specifically impairs respiratory responses dependent on Complexes II/III. Moreover, in the presence of multiple mitochondrial substrates, total respiratory capacity was decreased and reliance on pyruvate (Complex I)-fueled respiration was increased with BPM 31510 treatment, indicative of bioenergetic remodeling. Concomitantly to BPM 31510-dependent changes in mitochondrial respiratory responses, BPM 31510 exposure increased oxidation of the reactive oxygen species (ROS) probes, CellROX Green and DCF-DA, increased oxidized glutathione, and decreased levels of the cellular reducing equivalent NADPH. Importantly, BPM 31510-induced death could be partially rescued by agents which alleviate electron transport chain impairment linking respiratory function to the anti-cancer mechanism of action of BPM 31510. Together, these data indicate that BPM31510 directly impairs the mitochondrial Q-pool and respiratory function resulting in oxidative stress and consequential cell death and thus provide mechanistic understanding of the anti-cancer activity of BPM31510.
Citation Format: Pallavi Awate, Tulin Dadali, Ryan Ng, Saie Mogre, Anne R. Diers, Hannah Rockwell, Justice McDaniel, Emily Chen, Fei Gao, Michael Kiebish, Stephane Gesta, Vivek Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan. Coenzyme Q10 (BPM31510-IV in clinical trials) increases mitochondrial Q-pool and modulates electron transport chain function to elicit cell death in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3530.