Pecinova 2017 MiP2017
With increasing incidence of various cancer types, there is a growing need for development of new strategies for targeted treatments. Rapid growth and fast proliferation of some tumors require specific adaptations of cellular metabolism comprising high rates of glucose utilization and subsequent NADH reoxidation. In order to sustain high glycolytic rate, many cancer types depend on functional mitochondrial respiration (aerobic glycolysis). Here an important role is played by glycerophosphate shuttle, which represents one of the key cellular pathways for regeneration of cytosolic NAD+. Rate limiting component of the shuttle is mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase (mGPDH) - inducible and highly tissue/cell specific enzyme typically active in glycolytic cells. We identified prostate cancer cell lines as ones with high content and activity of mGPDH. Using novel mGPDH inhibitors (metformin, phenformin, alpha tocopheryl succinate and iGP-1) we targeted glycerophosphate shuttle in the tumor cells. Comparison of these compounds showed that iGP-1 and alpha tocopheryl succinate inhibit the enzyme in cell lines. However, solely the metformin treatment led to profound decrease of proliferation and increased apoptosis, compared to control cells.
Labels: MiParea: Pharmacology;toxicology Pathology: Cancer
Affiliations and support
- Dept Bioenergetics, Inst Physiol, Czech Academy Sciences, Prague, Czech Republic. - [email protected]
- Supported by the Czech Health Research Council (grant No. 15-28848A).