title: Targeting mitochondria as a therapeutic target in cancer.
abstract: Knowledge of re-programming in cancer cells with metabolic differences from their normal counterparts has resulted in new examination of therapeutic approaches. Several studies of the role of tumor mitochondria in cancer have led to the development of non-genotoxic therapies which target mitochondrial proteins, function. The now well-established functions of mitochondria in apoptosis provide novel targets for tumor cell suicide. Mitochondria serve as a central hub for responses to cellular stress as well as injury. The alterations in cancer cells which result in protection from apoptosis can be targeted to inhibit proliferation. Because of the reprogramming of cancer cell metabolism involving increased glycolysis, it appears that blocking InsP(3)R Ca(2+) release or adaptive pathways in response to hypoxia by targeting HIF-1 or metabolic enzymes encoded by the HIF-1 gene represents a feasible therapeutic approach to cancer. A very early in vitro event found in tumor cells following resveratrol addition is an increase in intracellular Ca(2+), measurable within seconds. Ca(2+) release is also observed with non-toxic flavonoids and a goal to identify the sentinel targets of resveratrol as a model compound involved in calcium activation seems worthwhile. New findings of the relationship between autophagy and apoptosis are discussed. The contribution of reactive oxygen species (ROS) generated by mitochondria is also considered. New data as to how cyclophilins and VDAC are involved in mitochondrial hexokinase protection of factors that induce apoptosis are reviewed. In addition, chemotherapeutic approaches based on Akt-activated mTORC1 are described, and their relationship to the role of aerobic glycolysis in this protection.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. charles.wenner@roswellpark.org
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wenner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents