title: Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection.
abstract: Selective modulation of cell death is important for rational chemotherapy. By depleting Hsp90-client oncoproteins, geldanamycin (GA) and 17-allylamino-17-demethoxy-GA (17-AAG) (heat-shock protein-90-active drugs) render certain oncoprotein-addictive cancer cells sensitive to chemotherapy. Here we investigated effects of GA and 17-AAG in apoptosis-prone cells such as HL60 and U937. In these cells, doxorubicin (DOX) caused rapid apoptosis, whereas GA-induced heat-shock protein-70 (Hsp70) (a potent inhibitor of apoptosis) and G1 arrest without significant apoptosis. GA blocked caspase activation and apoptosis and delayed cell death caused by DOX. Inhibitors of translation and transcription and siRNA Hsp70 abrogated cytoprotective effects of GA. Also GA failed to protect HL60 cells from cytotoxicity of actinomycin D and flavopiridol (FL), inhibitors of transcription. We next compared cytoprotection by GA-induced Hsp70, caspase inhibitors (Z-VAD-fmk) and cell-cycle arrest. Whereas cell-cycle arrest protected HL60 cells from paclitaxel (PTX) but not from FL and DOX, Z-VAD-fmk prevented FL-induced apoptosis but was less effective against DOX and PTX. Thus, by inducing Hsp70, GA protected apoptosis-prone cells in unique and cell-type selective manner. Since GA does not protect apoptosis-reluctant cancer cells, we envision a therapeutic strategy to decrease side effects of chemotherapy without affecting its therapeutic efficacy.
authors.affiliation: Brander Cancer Research Institute, New York Medical College, Valhalla, NY, USA.
authors.forename: Z N
authors.initials: ZN
authors.lastname: Demidenko
authors.forename: C
authors.initials: C
authors.lastname: Vivo
authors.forename: H D
authors.initials: HD
authors.lastname: Halicka
authors.forename: C J
authors.initials: CJ
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Bhalla
authors.forename: E V
authors.initials: EV
authors.lastname: Broude
authors.forename: M V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D061945:Caspase Inhibitors; D005419:Flavonoids; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010880:Piperidines; D034741:RNA, Small Interfering; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003609:Dactinomycin; C077990:alvocidib; C112765:tanespimycin; D004317:Doxorubicin; D053453:Caspase 9; D017239:Paclitaxel; C001277:geldanamycin