PT  - JOURNAL ARTICLE
AU  - Fabiola Cervantes-Gomez
AU  - Ramadevi Nimmanapalli
AU  - Varsha Gandhi
TI  - ATP analog enhances the actions of a HSP90 inhibitor in multiple myeloma cells
AID  - 10.1124/jpet.111.184903
DP  - 2011 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.111.184903
4099  - http://jpet.aspetjournals.org/content/early/2011/08/05/jpet.111.184903.short
4100  - http://jpet.aspetjournals.org/content/early/2011/08/05/jpet.111.184903.full
AB  - Heat shock protein 90 (HSP90) regulates client oncoprotein maturation. HSP90's chaperone function is blocked by 17-AAG, although it results in transcription and translation of antiapoptotic HSP proteins. Using three myeloma cell lines we tested if 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 STAT3, Raf-1, and Akt were analyzed. 17-AAG alone resulted in <10% change in STAT3, Raf-1, and Akt protein levels, while no change was observed for 4E-BP1. In contrast, the combination treatment resulted in >50% decrease of client protein levels and marked hypophosphorylation of 4E-BP1. 8-Cl-Ado alone resulted in <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 that targets transcription, translation and cellular bioenergy, enhanced 17-AAG-mediated cytotoxicity in myeloma cells.