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Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms

In this review, we focus on how inhibitors of Hsp90 can help prevent the resistance to anti-cancer drugs by synergistically increasing their cancer killing abilities and thereby allowing them to function at much lower concentrations than normally used. Hsp90 helps to fold numerous client proteins, s...

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Detalles Bibliográficos
Autores principales: Lu, Xiangyi, Wang, Luan, Ruden, Douglas M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816646/
https://www.ncbi.nlm.nih.gov/pubmed/24280696
http://dx.doi.org/10.3390/ph5090890
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author Lu, Xiangyi
Wang, Luan
Ruden, Douglas M.
author_facet Lu, Xiangyi
Wang, Luan
Ruden, Douglas M.
author_sort Lu, Xiangyi
collection PubMed
description In this review, we focus on how inhibitors of Hsp90 can help prevent the resistance to anti-cancer drugs by synergistically increasing their cancer killing abilities and thereby allowing them to function at much lower concentrations than normally used. Hsp90 helps to fold numerous client proteins, such as Akt, Raf, Src, chromatin-modifying proteins, nuclear hormone receptors, and kinetochore assembly proteins. We discuss four mechanisms by which Hsp90 inhibitors can potentially synergize with anti-cancer drugs: by making a drug-resistant protein that is a client for Hsp90 more sensitive to the drug, by increasing chromosomal aneuploidy and the effectiveness of DNA-damaging drugs, by inhibiting Trithorax proteins which trimethylate histone 3 at lysine 4 (H3K4me3) and thereby decreasing expression of tumor promoter genes, and by interacting with the negative elongation factor (NELF) complex in tumors. We also explain how the evolutionary capacitor function of Hsp90 can be exploited with inhibitors of Hsp90 by exposing new protein variants that can be targeted with other drugs, thereby opening new avenues of combination drug therapy to treat cancer. We believe that inhibition of these processes can increase the efficacy of Hsp90 inhibitors with other anti-cancer drugs.
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spelling pubmed-38166462013-11-14 Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms Lu, Xiangyi Wang, Luan Ruden, Douglas M. Pharmaceuticals (Basel) Review In this review, we focus on how inhibitors of Hsp90 can help prevent the resistance to anti-cancer drugs by synergistically increasing their cancer killing abilities and thereby allowing them to function at much lower concentrations than normally used. Hsp90 helps to fold numerous client proteins, such as Akt, Raf, Src, chromatin-modifying proteins, nuclear hormone receptors, and kinetochore assembly proteins. We discuss four mechanisms by which Hsp90 inhibitors can potentially synergize with anti-cancer drugs: by making a drug-resistant protein that is a client for Hsp90 more sensitive to the drug, by increasing chromosomal aneuploidy and the effectiveness of DNA-damaging drugs, by inhibiting Trithorax proteins which trimethylate histone 3 at lysine 4 (H3K4me3) and thereby decreasing expression of tumor promoter genes, and by interacting with the negative elongation factor (NELF) complex in tumors. We also explain how the evolutionary capacitor function of Hsp90 can be exploited with inhibitors of Hsp90 by exposing new protein variants that can be targeted with other drugs, thereby opening new avenues of combination drug therapy to treat cancer. We believe that inhibition of these processes can increase the efficacy of Hsp90 inhibitors with other anti-cancer drugs. MDPI 2012-08-30 /pmc/articles/PMC3816646/ /pubmed/24280696 http://dx.doi.org/10.3390/ph5090890 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Review
Lu, Xiangyi
Wang, Luan
Ruden, Douglas M.
Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms
title Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms
title_full Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms
title_fullStr Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms
title_full_unstemmed Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms
title_short Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms
title_sort hsp90 inhibitors and the reduction of anti-cancer drug resistance by non-genetic and genetic mechanisms
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816646/
https://www.ncbi.nlm.nih.gov/pubmed/24280696
http://dx.doi.org/10.3390/ph5090890
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