title: Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor.
abstract: Osteosarcoma (OS) is an aggressive bone cancer typically observed in adolescents and young adults. Metastatic relapse accounts primarily for treatment failure, and obstacles to improving cure rates include a lack of efficacious agents. Our studies show apoptosis of OS cells prepared from localized and metastatic tumors by a novel drug combination: SCH727965 (SCH), a cyclin-dependent kinase inhibitor, and NVP-AUY922 (AUY) or other heat shock protein 90 inhibitor. SCH and AUY induced apoptosis when added simultaneously to cells and when AUY was added to and removed from cells before SCH addition. Sequential treatment was most effective when cells received AUY for ~12 h and when SCH was presented to cells immediately after AUY removal. The apoptotic protein Bax accumulated in mitochondria of cotreated cells but was primarily cytosolic in cells receiving either agent alone. Additional data show that SCH and AUY cooperatively induce the apoptosis of other sarcoma cell types but not of normal osteoblasts or fibroblasts, and that SCH and AUY individually inhibit cell cycle progression throughout the cell cycle. We suggest that the combination of SCH and AUY may be an effective new strategy for treatment of OS.
authors.affiliation: Department of Molecular Oncology, Gonzmart Research Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: W
authors.initials: W
authors.lastname: Fu
authors.forename: S S
authors.initials: SS
authors.lastname: Sharma
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: B
authors.initials: B
authors.lastname: Chu
authors.forename: M M
authors.initials: MM
authors.lastname: Bui
authors.forename: D
authors.initials: D
authors.lastname: Reed
authors.forename: W J
authors.initials: WJ
authors.lastname: Pledger
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001859:Bone Neoplasms / Q000188:drug therapy; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007212:Indolizines; D007555:Isoxazoles / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D021381:Protein Transport; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C494826:BAX protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D018841:HSP90 Heat-Shock Proteins; D007212:Indolizines; D007555:Isoxazoles; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; D012118:Resorcinols; D051028:bcl-2-Associated X Protein; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases
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