Cisplatin abrogates the geldanamycin-induced heat shock response

Andrea K. McCollum, Kara B. Lukasiewicz, Cynthia J. TenEyck, Wilma L. Lingle, David O. Toft, Charles Erlichman

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Abstract

Benzoquinone ansamycin antibiotics such as geldanamycin (GA) bind to the NH2-terminal ATP-binding domain of heat shock protein (Hsp) 90 and inhibit its chaperone functions. Despite in vitro and in vivo studies indicating promising antitumor activity, derivatives of GA, including 17- allylaminogeldanamycin (17-AAG), have shown little clinical efficacy as single agents. Thus, combination studies of 17-AAG and several cancer chemotherapeutics, including cisplatin (CDDP), have begun. In colony-forming assays, the combination of CDDP and GA or 17-AAG was synergistic and caused increased apoptosis compared with each agent alone. One measurable response that results from treatment with Hsp90-targeted agents is the induction of a heat shock factor-1 (HSF-1) heat shock response. Treatment with GA + CDDP revealed that CDDP suppresses up-regulation of HSF-1 transcription, causing decreased levels of stress-inducible proteins such as Hsp27 and Hsp70. However, CDDP treatment did not prevent trimerization and nuclear localization of HSF-1 but inhibited DNA binding of HSF-1 as shown by chromatin immunoprecipitation. Melphalan, but not camptothecin, caused similar inhibition of GA-induced HSF-1-mediated Hsp70 up-regulation. 3-(4,5-Dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt cell survival assays revealed that deletion of Hsp70 caused increased sensitivity to GA (Hsp70 +/+ IC50 = 63.7 ± 14.9 nmol/L and Hsp70 -/- IC50 = 4.3 ± 2.9 nmol/L), which confirmed that a stress response plays a critical role in decreasing GA sensitivity. Our results suggest that the synergy of GA + CDDP is due, in part, to CDDP-mediated abrogation of the heat shock response through inhibition of HSF-1 activity. Clinical modulation of the HSF-1-mediated heat shock response may enhance the efficacy of Hsp90-directed therapy.

Original languageEnglish (US)
Pages (from-to)3256-3264
Number of pages9
JournalMolecular Cancer Therapeutics
Volume7
Issue number10
DOIs
StatePublished - Oct 1 2008

Fingerprint

Heat-Shock Response
Cisplatin
tanespimycin
Shock
Hot Temperature
Inhibitory Concentration 50
Up-Regulation
Rifabutin
Tetrazolium Salts
HSP90 Heat-Shock Proteins
Camptothecin
Melphalan
geldanamycin
Chromatin Immunoprecipitation
Heat-Shock Proteins
Cell Survival
Adenosine Triphosphate
Apoptosis
Anti-Bacterial Agents
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McCollum, A. K., Lukasiewicz, K. B., TenEyck, C. J., Lingle, W. L., Toft, D. O., & Erlichman, C. (2008). Cisplatin abrogates the geldanamycin-induced heat shock response. Molecular Cancer Therapeutics, 7(10), 3256-3264. https://doi.org/10.1158/1535-7163.MCT-08-0157

Cisplatin abrogates the geldanamycin-induced heat shock response. / McCollum, Andrea K.; Lukasiewicz, Kara B.; TenEyck, Cynthia J.; Lingle, Wilma L.; Toft, David O.; Erlichman, Charles.

In: Molecular Cancer Therapeutics, Vol. 7, No. 10, 01.10.2008, p. 3256-3264.

Research output: Contribution to journalArticle

McCollum, AK, Lukasiewicz, KB, TenEyck, CJ, Lingle, WL, Toft, DO & Erlichman, C 2008, 'Cisplatin abrogates the geldanamycin-induced heat shock response', Molecular Cancer Therapeutics, vol. 7, no. 10, pp. 3256-3264. https://doi.org/10.1158/1535-7163.MCT-08-0157
McCollum AK, Lukasiewicz KB, TenEyck CJ, Lingle WL, Toft DO, Erlichman C. Cisplatin abrogates the geldanamycin-induced heat shock response. Molecular Cancer Therapeutics. 2008 Oct 1;7(10):3256-3264. https://doi.org/10.1158/1535-7163.MCT-08-0157
McCollum, Andrea K. ; Lukasiewicz, Kara B. ; TenEyck, Cynthia J. ; Lingle, Wilma L. ; Toft, David O. ; Erlichman, Charles. / Cisplatin abrogates the geldanamycin-induced heat shock response. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 10. pp. 3256-3264.
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