Celecoxib inhibits mitochondrial O2 consumption, promoting ROS dependent death of murine and human metastatic cancer cells via the apoptotic signalling pathway
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Rodriguez-Enriquez, Sara
Cecilia Pacheco-Velazquez, Silvia
Bortnik, Vuk
Moreno-Sanchez, Rafael
Ralph, Stephen
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Abstract
Capecitabine induced toxicities such as hand-foot syndrome (HFS) and progression of metastatic cancer are both treatable with concurrent celecoxib as shown in the ADAPT (Activating Cancer Stem Cells from Dormancy And Potentiate for Targeting) trial. In the present study, five commonly used NSAIDs, including celecoxib were compared for their pro-oxidative capacities as cytotoxic drugs against human and mouse metastatic melanoma or breast cancer cells in vitroand the source of cellular ROS production induced by celecoxib was examined in greater detail.
Results: Celecoxib was unique among the NSAIDs in that it showed particular potency as a cytotoxic drug against the metastatic cancer cells with IC50 values in the low micromolar range. Celecoxib rapidly enhanced mitochondrial superoxide production in situ from cancer cells within minutes, leading to a decrease in cellular respiration and dissipation of the mitochondrial transmembrane potential (Δψm), followed by extensive ROS-dependent apoptosis of the metastatic cancer cells. Celecoxib also showed rapid and direct effects on isolated mitochondria, inducing extensive ROS production in a dose-dependent manner, whilst it inhibited respiration via Complex I or Complex II when tested in whole cells. Mitochondrial ROS production was necessary for the celecoxib induced cell death.
Innovation and Conclusion: These novel findings for direct effects of celecoxib on mitochondria to induce metastatic cancer cell death via a ROS-dependent pro-oxidative mechanism provide supportive evidence for its combinatorial use as a chemosensitizing agent complementing chemotherapies to improve response rates in patients with advanced metastatic cancers.
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Biochemical Pharmacology
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154
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© 2018 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
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Biochemistry and cell biology
Pharmacology and pharmaceutical sciences
Pharmacology and pharmaceutical sciences not elsewhere classified