Cisplatin abrogates the geldanamycin-induced heat shock response.

Cisplatin abrogates the geldanamycin-induced heat shock response. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Cisplatin abrogates the geldanamycin-induced heat shock response. Abstract Text:

Benzoquinone ansamycin antibiotics such as geldanamycin (GA) bind to the NH(2)-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(+/+) IC(50) = 63.7 +/- 14.9 nmol/L and Hsp70(-/-) IC(50) = 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. [Mol Cancer Ther 2008;7(10):3256-64].

Cisplatin abrogates the geldanamycin-induced heat shock response. Publishing Authors By Initials

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

Cisplatin abrogates the geldanamycin-induced heat shock response. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Molecular cancer therapeutics

VOLUME: 7

Page Numbers: 3256-64

Journal Abbreviation:

ISSN: 1535-7163

DAY: 14

MONTH: Oct

YEAR: 2008

Cisplatin abrogates the geldanamycin-induced heat shock response. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101132535

Cisplatin abrogates the geldanamycin-induced heat shock response. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: Cisplatin abrogates the geldanamycin-induced heat shock response. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for Cisplatin abrogates the geldanamycin-induced heat shock response.

AFFILIATION: Department of Oncology, Guggenheim 1311A, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905. erlichman.charles@mayo.edu.

Country: United States

AGENCY:

GRANT:

ACRONYM:

MEDLINETA: Mol Cancer Ther

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Cisplatin abrogates the geldanamycin-induced heat shock response Related Publications

• A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors.
• An overview of the clinical pharmacology of N-phosphonacetyl-L-aspartate (PALA), a new antimetabolite.
• Cisplatin abrogates the geldanamycin-induced heat shock response.
• Dysphagia research in the 21st century and beyond: proceedings from Dysphagia Experts Meeting, August 21, 2001.
• HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924.
• P-glycoprotein-mediated resistance to hsp90-directed therapy is eclipsed by the heat shock response.
• Phase II trial of oxaliplatin/irinotecan/5-fluorouracil/leucovorin for metastatic colorectal cancer.
• Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism.