ArticleCancer research2008
P-Glycoprotein-mediated resistance to Hsp90-directed therapy is eclipsed by the heat shock response.
Article in Cancer research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
28 citing papers in PubMed, 75 citations in OpenAlex.
- Hsp90Pharmaceuticals (Basel, Switzerland) · 2025Review
- A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication.Signal transduction and targeted therapy · 2024Article
- The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer.Theranostics · 2024Article
- The heat shock response and small molecule regulators.European journal of medicinal chemistry · 2021Review
- Heat Shock Protein Inhibitor 17-Allyamino-17-Demethoxygeldanamycin, a Potent Inductor of Apoptosis in Human Glioma Tumor Cell Lines, Is a Weak Substrate for ABCB1 and ABCG2 Transporters.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling.Frontiers in oncology · 2021Article
- Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.International journal of molecular sciences · 2019Article
- Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors.Molecular oncology · 2017Article
- Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1.Oncotarget · 2015Article
- Bioactive metabolites from Chaetomium aureum: structure elucidation and inhibition of the Hsp90 machine chaperoning activity.Bioorganic & medicinal chemistry · 2015Article
- Comparative Study of 17-AAG and NVP-AUY922 in Pancreatic and Colorectal Cancer Cells: Are There Common Determinants of Sensitivity?Translational oncology · 2014Article
- Preclinical antitumor activity of SST0116CL1: a novel heat shock protein 90 inhibitor.International journal of oncology · 2014Article
- Contributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity.Future medicinal chemistry · 2013Review
- Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy.Current molecular medicine · 2012Review
- Development of a Grp94 inhibitor.Journal of the American Chemical Society · 2012Article
- Corresponding functional dynamics across the Hsp90 Chaperone family: insights from a multiscale analysis of MD simulations.PLoS computational biology · 2012Article
- Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia.Haematologica · 2011Article
- Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges.Pharmaceuticals (Basel, Switzerland) · 2011Review
- Transport processes of radiopharmaceuticals and -modulators.Radiation oncology (London, England) · 2011Review
- Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors.Investigational new drugs · 2011Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.