title: Can the therapeutic effects of temozolomide be potentiated by stimulating AMP-activated protein kinase with olanzepine and metformin?
abstract: As current treatments for glioblastoma commonly fail to cure, the need for more effective therapeutic options is overwhelming. Here, we summarize experimental evidence in support of the suggestion that metformin and olanzepine have potential to enhance the cytotoxic effects of temozolomide, an alkylating chemotherapeutic agent commonly used to treat glioblastoma. Although the primary path leading to temozolomide-induced cell death is formation of O-6-methylguanine and apoptotic signalling triggered by O-6-methyl G:T mispairs, that apoptotic signalling goes through a step mediated by AMP-activated protein kinase (AMPK). Metformin or olanzapine have been shown independently to enhance AMPK activation. Metformin to treat diabetes and olanzapine to treat psychiatric disorders are well tolerated and have been used clinically for many years. Thus it should be feasible to increase AMPK activation and add to the pro-apoptotic effects of temozolomide, by adding metformin and olanzapine to the therapeutic regimen. Clinical assessment of the potential benefit of such combined therapy against glioblastoma is warranted.
authors.affiliation: Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA. rekast@email.com
authors.forename: R E
authors.initials: RE
authors.lastname: Kast
authors.forename: G
authors.initials: G
authors.lastname: Karpel-Massler
authors.forename: M-E
authors.initials: ME
authors.lastname: Halatsch
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D000077152:Olanzapine; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001569:Benzodiazepines; D003606:Dacarbazine; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000077152:Olanzapine; D000077204:Temozolomide