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Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines

Heat shock protein 90 (HSP90) facilitates folding and stability and prevents the degradation of multiple client proteins. One of these HSP90 clients is BCR-ABL, the oncoprotein characteristic of chronic myeloid leukemia (CML) and the target of tyrosine kinase inhibitors, such as imatinib. Alvespimyc...

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Autores principales: Alves, Raquel, Santos, Diogo, Jorge, Joana, Gonçalves, Ana Cristina, Catarino, Steve, Girão, Henrique, Melo, Joana Barbosa, Sarmento-Ribeiro, Ana Bela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9920317/
https://www.ncbi.nlm.nih.gov/pubmed/36770876
http://dx.doi.org/10.3390/molecules28031210
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author Alves, Raquel
Santos, Diogo
Jorge, Joana
Gonçalves, Ana Cristina
Catarino, Steve
Girão, Henrique
Melo, Joana Barbosa
Sarmento-Ribeiro, Ana Bela
author_facet Alves, Raquel
Santos, Diogo
Jorge, Joana
Gonçalves, Ana Cristina
Catarino, Steve
Girão, Henrique
Melo, Joana Barbosa
Sarmento-Ribeiro, Ana Bela
author_sort Alves, Raquel
collection PubMed
description Heat shock protein 90 (HSP90) facilitates folding and stability and prevents the degradation of multiple client proteins. One of these HSP90 clients is BCR-ABL, the oncoprotein characteristic of chronic myeloid leukemia (CML) and the target of tyrosine kinase inhibitors, such as imatinib. Alvespimycin is an HSP90 inhibitor with better pharmacokinetic properties and fewer side effects than other similar drugs, but its role in overcoming imatinib resistance is not yet clarified. This work studied the therapeutic potential of alvespimycin in imatinib-sensitive (K562) and imatinib-resistant (K562-RC and K562-RD) CML cell lines. Metabolic activity was determined by the resazurin assay. Cell death, caspase activity, mitochondrial membrane potential, and cell cycle were evaluated by means of flow cytometry. Cell death was also analyzed by optical microscopy. HSPs expression levels were assessed by western blotting. Alvespimycin reduced metabolic activity in a time-, dose-, and cell line-dependent manner. Resistant cells were more sensitive to alvespimycin with an IC(50) of 31 nM for K562-RC and 44 nM for K562-RD, compared to 50 nM for K562. This drug induced apoptosis via the mitochondrial pathway. In K562 cells, alvespimycin induced cell cycle arrest in G(0)/G(1). As a marker of HSP90 inhibition, a significant increase in HSP70 expression was observed. Our results suggest that alvespimycin might be a new therapeutic approach to CML treatment, even in cases of resistance to imatinib.
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spelling pubmed-99203172023-02-12 Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines Alves, Raquel Santos, Diogo Jorge, Joana Gonçalves, Ana Cristina Catarino, Steve Girão, Henrique Melo, Joana Barbosa Sarmento-Ribeiro, Ana Bela Molecules Article Heat shock protein 90 (HSP90) facilitates folding and stability and prevents the degradation of multiple client proteins. One of these HSP90 clients is BCR-ABL, the oncoprotein characteristic of chronic myeloid leukemia (CML) and the target of tyrosine kinase inhibitors, such as imatinib. Alvespimycin is an HSP90 inhibitor with better pharmacokinetic properties and fewer side effects than other similar drugs, but its role in overcoming imatinib resistance is not yet clarified. This work studied the therapeutic potential of alvespimycin in imatinib-sensitive (K562) and imatinib-resistant (K562-RC and K562-RD) CML cell lines. Metabolic activity was determined by the resazurin assay. Cell death, caspase activity, mitochondrial membrane potential, and cell cycle were evaluated by means of flow cytometry. Cell death was also analyzed by optical microscopy. HSPs expression levels were assessed by western blotting. Alvespimycin reduced metabolic activity in a time-, dose-, and cell line-dependent manner. Resistant cells were more sensitive to alvespimycin with an IC(50) of 31 nM for K562-RC and 44 nM for K562-RD, compared to 50 nM for K562. This drug induced apoptosis via the mitochondrial pathway. In K562 cells, alvespimycin induced cell cycle arrest in G(0)/G(1). As a marker of HSP90 inhibition, a significant increase in HSP70 expression was observed. Our results suggest that alvespimycin might be a new therapeutic approach to CML treatment, even in cases of resistance to imatinib. MDPI 2023-01-26 /pmc/articles/PMC9920317/ /pubmed/36770876 http://dx.doi.org/10.3390/molecules28031210 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alves, Raquel
Santos, Diogo
Jorge, Joana
Gonçalves, Ana Cristina
Catarino, Steve
Girão, Henrique
Melo, Joana Barbosa
Sarmento-Ribeiro, Ana Bela
Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines
title Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines
title_full Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines
title_fullStr Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines
title_full_unstemmed Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines
title_short Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines
title_sort alvespimycin inhibits heat shock protein 90 and overcomes imatinib resistance in chronic myeloid leukemia cell lines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9920317/
https://www.ncbi.nlm.nih.gov/pubmed/36770876
http://dx.doi.org/10.3390/molecules28031210
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