title: ABT-263 enhances sensitivity to metformin and 2-deoxyglucose in pediatric glioma by promoting apoptotic cell death.
abstract: Pediatric high grade glioma is refractory to conventional multimodal treatment, highlighting a need to develop novel efficacious therapies. We investigated tumor metabolism as a potential therapeutic target in a panel of diverse pediatric glioma cell lines (SF188, KNS42, UW479 and RES186) using metformin and 2-deoxyglucose. As a single agent, metformin had little effect on cell viability overall. SF188 cells were highly sensitive to 2-deoxyglucose however, combination of metformin with 2-deoxyglucose significantly reduced cell proliferation compared to either drug alone in all cell lines tested. In addition, the combination of the two agents was associated with a rapid decrease in cellular ATP and subsequent AMPK activation. However, increased cell death was only observed in select cell lines after prolonged exposure to the drug combination and was caspase independent. Anti-apoptotic BCL-2 family proteins have been indicated as mediators of resistance against metabolic stress. Therefore we sought to determine whether pharmacological inhibition of BCL-2/BCL-xL with ABT-263 could potentiate apoptosis in response to these agents. We found that ABT-263 increased sensitivity to 2-deoxyglucose and promoted rapid and extensive cell death in response to the combination of 2-deoxyglucose and metformin. Furthermore, cell death was inhibited by the pan-caspase inhibitor, z-VAD-FMK suggesting that ABT-263 potentiated caspase-dependent cell death in response to 2-deoxyglucose or its combination with metformin. Overall, these data provide support for the concept that targeting metabolic and anti-apoptotic pathways may be an effective therapeutic strategy in pediatric glioma.
authors.affiliation: Translational Neuro-Oncology Group, Leeds Institute of Molecular Medicine, University of Leeds, St James's University Hospital, Leeds, United Kingdom. j.levesley@leeds.ac.uk
authors.forename: Jane
authors.initials: J
authors.lastname: Levesley
authors.forename: Lynette
authors.initials: L
authors.lastname: Steele
authors.forename: Claire
authors.initials: C
authors.lastname: Taylor
authors.forename: Priyank
authors.initials: P
authors.lastname: Sinha
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008687:Metformin / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000814:Aniline Compounds; D013449:Sulfonamides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000255:Adenosine Triphosphate; D008687:Metformin; D003847:Deoxyglucose; D020169:Caspases; C528561:navitoclax