title: Overcoming hypoxia-induced apoptotic resistance through combinatorial inhibition of GSK-3β and CDK1.
abstract: Tumor hypoxia is an inherent impediment to cancer treatment that is both clinically significant and problematic. In this study, we conducted a cell-based screen to identify small molecules that could reverse the apoptotic resistance of hypoxic cancer cells. Among the compounds, we identified were a structurally related group that sensitized hypoxic cancer cells to apoptosis by inhibiting the kinases GSK-3β and cyclin-dependent kinase (CDK) 1. Combinatorial inhibition of these proteins in hypoxic cancer cells and tumors increased levels of c-Myc and decreased expression of c-IAP2 and the central hypoxia response regulator hypoxia-inducible factor (HIF) 1α. In mice, these compounds augmented the hypoxic tumor cell death induced by cytotoxic chemotherapy, blocking angiogenesis and tumor growth. Taken together, our findings suggest that combinatorial inhibition of GSK-3β and CDK1 augment the apoptotic sensitivity of hypoxic tumors, and they offer preclinical validation of a novel and readily translatable strategy to improve cancer therapy.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Mayes
authors.forename: Nathan G
authors.initials: NG
authors.lastname: Dolloff
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Daniel
authors.forename: J Judy
authors.initials: JJ
authors.lastname: Liu
authors.forename: Lori S
authors.initials: LS
authors.lastname: Hart
authors.forename: Kageaki
authors.initials: K
authors.lastname: Kuribayashi
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Allen
authors.forename: David I H
authors.initials: DI
authors.lastname: Jee
authors.forename: Jay F
authors.initials: JF
authors.lastname: Dorsey
authors.forename: Yingqiu Y
authors.initials: YY
authors.lastname: Liu
authors.forename: David T
authors.initials: DT
authors.lastname: Dicker
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000502:physiology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000637:transplantation; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000502:physiology; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020598:Proto-Oncogene Proteins c-myb / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D020598:Proto-Oncogene Proteins c-myb; D011743:Pyrimidines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D016203:CDC2 Protein Kinase; D038362:Glycogen Synthase Kinase 3; D005472:Fluorouracil; D002166:Camptothecin