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Elevated levels of mitochondrial CoQ₁₀ induce ROS-mediated apoptosis in pancreatic cancer.

ABSTRACT: Reactive oxygen species (ROS) are implicated in triggering cell signalling events and pathways to promote and maintain tumorigenicity. Chemotherapy and radiation can induce ROS to elicit cell death allows for targeting ROS pathways for effective anti-cancer therapeutics. Coenzyme Q₁₀ is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration. This study demonstrates that delivery of oxidized Coenzyme Q₁₀ (ubidecarenone) to increase mitochondrial Q-pool is associated with an increase in ROS generation, effectuating anti-cancer effects in a pancreatic cancer model. Consequent activation of cell death was observed in vitro in pancreatic cancer cells, and both human patient-derived organoids and tumour xenografts. The study is a first to demonstrate the effectiveness of oxidized ubidecarenone in targeting mitochondrial function resulting in an anti-cancer effect. Furthermore, these findings support the clinical development of proprietary formulation, BPM31510, for treatment of cancers with high ROS burden with potential sensitivity to ubidecarenone.

SUBMITTER: Dadali T

PROVIDER: S-EPMC7952582 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Elevated levels of mitochondrial CoQ10 induce ROS-mediated apoptosis in pancreatic cancer.

Dadali Tulin T Diers Anne R AR Kazerounian Shiva S Muthuswamy Senthil K SK Awate Pallavi P Ng Ryan R Mogre Saie S Spencer Carrie C Krumova Katerina K Rockwell Hannah E HE McDaniel Justice J Chen Emily Y EY Gao Fei F Diedrich Karl T KT Vemulapalli Vijetha V Rodrigues Leonardo O LO Akmaev Viatcheslav R VR Thapa Khampaseuth K Hidalgo Manuel M Bose Arindam A Vishnudas Vivek K VK Moser A James AJ Granger Elder E Kiebish Michael A MA Gesta Stephane S Narain Niven R NR Sarangarajan Rangaprasad R

Scientific reports 20210311 1

Reactive oxygen species (ROS) are implicated in triggering cell signalling events and pathways to promote and maintain tumorigenicity. Chemotherapy and radiation can induce ROS to elicit cell death allows for targeting ROS pathways for effective anti-cancer therapeutics. Coenzyme Q10 is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration. This study demonstrates that delivery of oxidized Coenzyme Q10</ ...[more]

PMID: 33707480

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Project description:BackgroundOxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis.Study designPlacebo-controlled, 3-arm, double-blind, randomized, clinical trial.Setting & participants65 patients undergoing thrice-weekly maintenance hemodialysis.InterventionPatients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10; 600 or 1,200mg) or matching placebo for 4 months.OutcomesThe primary outcome was plasma oxidative stress, defined as plasma concentration of F2-isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability.MeasurementsF2-isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro-brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months.ResultsOf 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200mg, but not 600mg, of CoQ10 significantly reduced plasma F2-isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of -10.7 [95% CI, -7.1 to -14.3] pg/mL [P<0.001] and -8.3 [95% CI, -5.5 to -11.0] pg/mL [P=0.1], respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures.LimitationsStudy not powered to detect small treatment effects; difference in baseline characteristics among randomized groups.ConclusionsIn patients undergoing maintenance hemodialysis, daily supplementation with 1,200mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2-isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.

Dataset Information

Elevated levels of mitochondrial CoQ₁₀ induce ROS-mediated apoptosis in pancreatic cancer.

Publications

Elevated levels of mitochondrial CoQ<sub>10</sub> induce ROS-mediated apoptosis in pancreatic cancer.

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