P-glycoprotein-mediated resistance to hsp90-directed therapy is eclipsed by the heat shock response.

P-glycoprotein-mediated resistance to hsp90-directed therapy is eclipsed by the heat shock response. Research Abstract Details 

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P-glycoprotein-mediated resistance to hsp90-directed therapy is eclipsed by the heat shock response. Abstract Text:

Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) and its derivative 17-allylamino-demethoxygeldanamycin (17-AAG), recent reports indicate that these inhibitors lack significant single-agent clinical activity. Resistance to Hsp90 inhibitors has been previously linked to expression of P-glycoprotein (P-gp) and the multidrug resistant (MDR) phenotype. However, the stress response induced by GA treatment can also cause resistance to Hsp90-targeted therapy. Therefore, we chose to further investigate the relative importance of P-gp and the stress response in 17-AAG resistance. Colony-forming assays revealed that high expression of P-gp could increase the 17-AAG IC(50) 6-fold in cells transfected with P-gp compared with parent cells. A549 cells selected for resistance to GA overexpressed P-gp, but verapamil did not reverse the resistance. These cells also overexpressed Hsp27, and Hsp70 was induced with 17-AAG treatment. When the GA and 17-AAG resistant cells were transfected with Hsp27 and/or Hsp70 small interfering RNA (siRNA), the 17-AAG IC(50) decreased 10-fold compared with control transfected cells. Transfection with siRNA directed against Hsp27, Hsp70, or Hsp27 and Hsp70 also increased sensitivity to EC78, a purine scaffold-based Hsp90 inhibitor that is not a P-gp substrate. We conclude that P-gp may contribute, in part, to resistance to 17-AAG, but induction of stress response proteins, such as Hsp27 and Hsp70, by Hsp90-targeted therapy plays a larger role. Taken together, our results indicate that targeting of Hsp27 and Hsp70 should be exploited to increase the clinical efficacy of Hsp90-directed therapy. [Cancer Res 2008;68(18):7419-27].

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P-glycoprotein-mediated resistance to hsp90-directed therapy is eclipsed by the heat shock response. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Cancer research

VOLUME: 68

Page Numbers: 7419-27

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 15

MONTH: Sep

YEAR: 2008

P-glycoprotein-mediated resistance to hsp90-directed therapy is eclipsed by the heat shock response. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

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Grant and Affiliation Information for P-glycoprotein-mediated resistance to hsp90-directed therapy is eclipsed by the heat shock response.

AFFILIATION: Departments of Molecular Pharmacology and Experimental Therapeutics, Biochemistry and Molecular Biology, Cancer Center Statistics, Laboratory Medicine and Pathology, and Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Country: United States

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MEDLINETA: Cancer Res

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