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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

ATP Analog Enhances the Actions of a Heat Shock Protein 90 Inhibitor in Multiple Myeloma Cells

Fabiola Cervantes-Gomez, Ramadevi Nimmanapalli and Varsha Gandhi
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 545-554; DOI: https://doi.org/10.1124/jpet.111.184903
Fabiola Cervantes-Gomez
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Ramadevi Nimmanapalli
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Varsha Gandhi
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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.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grants Lymphoma SPORE CA136411, Myeloma SPORE CA142509].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.184903.

  • ABBREVIATIONS:

    HSP
    heat shock protein
    17-AAG
    17-N-allylamino-17-demethoxygeldanamycin
    HSF-1
    heat shock factor
    MM
    multiple myeloma
    8-Cl-Ado
    8-chloro-adenosine
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    STAT
    signal transducer and activator of transcription
    mTor
    mammalian target of rapamycin.

  • Received June 22, 2011.
  • Accepted August 3, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

8-Cl-Ado Enhances the Actions of 17-AAG in Myeloma Cells

Fabiola Cervantes-Gomez, Ramadevi Nimmanapalli and Varsha Gandhi
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 545-554; DOI: https://doi.org/10.1124/jpet.111.184903

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

8-Cl-Ado Enhances the Actions of 17-AAG in Myeloma Cells

Fabiola Cervantes-Gomez, Ramadevi Nimmanapalli and Varsha Gandhi
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 545-554; DOI: https://doi.org/10.1124/jpet.111.184903
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