title: ATP analog enhances the actions of a heat shock protein 90 inhibitor in multiple myeloma cells.
abstract: Heat shock protein (HSP) 90 regulates client oncoprotein maturation. The chaperone function of HSP90 is blocked by 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), although it results in transcription and translation of antiapoptotic HSP proteins. Using three myeloma cell lines, we tested whether inhibition of transcription/translation of HSP or client proteins will enhance 17-AAG-mediated cytotoxicity. 8-Chloro-adenosine (8-Cl-Ado), currently in clinical trials, inhibits bioenergy production, mRNA transcription, and protein translation and was combined with 17-AAG. 17-AAG treatment resulted in HSP transcript and protein level elevation. In the combination, 8-Cl-Ado did not abrogate HSP mRNA and protein induction. HSP90 requires ATP to stabilize client proteins; hence, expression of signal transducer and activator of transcription 3 (STAT3), Raf-1, and Akt was analyzed. 17-AAG alone resulted in <10% change in STAT3, Raf-1, and Akt protein levels, whereas no change was observed for 4E-BP1. In contrast, the combination treatment resulted in a >50% decrease in client protein levels and marked hypophosphorylation of 4E-BP1. 8-Cl-Ado alone resulted in a <30% decrease of client proteins and 4E-BP1 hypophosphorylation. 8-Cl-Ado combined with 17-AAG resulted in more than additive cytotoxicity. In conclusion, 8-Cl-Ado, which targets transcription, translation, and cellular bioenergy, enhanced 17-AAG-mediated cytotoxicity in myeloma cells.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Cervantes-Gomez
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Nimmanapalli
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D048490:raf Kinases
chemical_list: C479978:8-chlorodeoxyadenosine; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D003839:Deoxyadenosines; C087000:EIF4EBP1 protein, human; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010750:Phosphoproteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C112765:tanespimycin; D012313:RNA; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases