NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy

Intermittent hypoxia within tumor microenvironments causes pro-oxidative stress impairing oxidative phos-phorylation(OxPhos)and increases mitochondrial production of reactive oxygen species(ROS).In primary tu-mors this provokes metabolic reprogramming of both tumor cells and cancer stem cells and emergence of highly metastatic cancer cells.Tumor reprogramming is initiated by activating nuclear respiratory factors and hypoxia-inducible factors in response to changes in oxygen and ROS levels.Hence,hypoxia-induced pro-oxidative stress drives invasion and metastasis.However,it is also the Achilles’heel of metastatic cancer cells because pro-oxi-dative agents further overload the mitochondria and intracellular milieu with excessive ROS to trigger apoptosis,whereas antioxidant agents promote their survival and tumor progression.Herein lies the metastatic tumor cell sensitivity to non-steroidal anti-inflammatory drugs(NSAIDs)and we and others have shown that the NSAID celecoxib exerts powerful pro-oxidative anticancer effects by directly targeting mitochondria to increase ROS production and trigger cancer cell death,including metastatic cancer cells and cancer stem cells.This review highlights the considerable benefits from appropriate NSAID use in humans against post-diagnosis metastatic tumors and the need to further develop their use as adjuvant therapy for advanced stage metastatic disease where they are already showing significantly improved clinical outcomes.