Many conventional anticancer drugs have an associated lack of safety by their toxicity. Relatively faster mutations in tumor cells pose a significant obstacle in treatment of cancer. Recently, “Mitocans” have emerge...Many conventional anticancer drugs have an associated lack of safety by their toxicity. Relatively faster mutations in tumor cells pose a significant obstacle in treatment of cancer. Recently, “Mitocans” have emerged as a novel class of anticancer agents selectively targeting tumor cells and thus, are much less toxic than conventional anticancer chemotherapeutic agents. Mitocans are drugs that act directly on mitochondria within the cell, thus causing changes in energy metabolism of the cell. Amongst these mitocans, α-Tocopheryl succinate or vitamin E analogs are studied very well by researchers. This review discusses mitochondrial drug targeting strategies and a variety of novel mitochondrial drug targets of mitocans, such as electron transport chain, mitochondrial permeability transition, Bcl-2 family proteins and mitochondrial DNA. The purpose of this review is to focus on the various classes of mitocans, the mechanisms by which these drugs specifically act on tumor cells and their applications in cancer chemotherapeutics.展开更多
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 thi...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.展开更多
文摘Many conventional anticancer drugs have an associated lack of safety by their toxicity. Relatively faster mutations in tumor cells pose a significant obstacle in treatment of cancer. Recently, “Mitocans” have emerged as a novel class of anticancer agents selectively targeting tumor cells and thus, are much less toxic than conventional anticancer chemotherapeutic agents. Mitocans are drugs that act directly on mitochondria within the cell, thus causing changes in energy metabolism of the cell. Amongst these mitocans, α-Tocopheryl succinate or vitamin E analogs are studied very well by researchers. This review discusses mitochondrial drug targeting strategies and a variety of novel mitochondrial drug targets of mitocans, such as electron transport chain, mitochondrial permeability transition, Bcl-2 family proteins and mitochondrial DNA. The purpose of this review is to focus on the various classes of mitocans, the mechanisms by which these drugs specifically act on tumor cells and their applications in cancer chemotherapeutics.
基金This work was partially supported by CONACyT-Mexico grants No.239930 and 281428 to RMS and 283144 to SRE.Rhys Pritchard was supported by an Australian postgraduate research award(APRA).
文摘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.
