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Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events

Proteasome inhibitors, e.g. Bortezomib (BTZ) and Carfilzomib (CFZ), have demonstrated clinical efficacy against haematological cancers. Interestingly, several adverse effects are less common, compared to BTZ, in patients treated with CFZ. As the molecular details of these observations remain not wel...

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Autores principales: Tsakiri, Eleni N., Terpos, Evangelos, Papanagnou, Eleni-Dimitra, Kastritis, Efstathios, Brieudes, Vincent, Halabalaki, Maria, Bagratuni, Tina, Florea, Bogdan I., Overkleeft, Herman S., Scorrano, Luca, Skaltsounis, Alexios-Leandros, Dimopoulos, Meletios A., Trougakos, Ioannis P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736585/
https://www.ncbi.nlm.nih.gov/pubmed/29259189
http://dx.doi.org/10.1038/s41598-017-17596-4
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author Tsakiri, Eleni N.
Terpos, Evangelos
Papanagnou, Eleni-Dimitra
Kastritis, Efstathios
Brieudes, Vincent
Halabalaki, Maria
Bagratuni, Tina
Florea, Bogdan I.
Overkleeft, Herman S.
Scorrano, Luca
Skaltsounis, Alexios-Leandros
Dimopoulos, Meletios A.
Trougakos, Ioannis P.
author_facet Tsakiri, Eleni N.
Terpos, Evangelos
Papanagnou, Eleni-Dimitra
Kastritis, Efstathios
Brieudes, Vincent
Halabalaki, Maria
Bagratuni, Tina
Florea, Bogdan I.
Overkleeft, Herman S.
Scorrano, Luca
Skaltsounis, Alexios-Leandros
Dimopoulos, Meletios A.
Trougakos, Ioannis P.
author_sort Tsakiri, Eleni N.
collection PubMed
description Proteasome inhibitors, e.g. Bortezomib (BTZ) and Carfilzomib (CFZ), have demonstrated clinical efficacy against haematological cancers. Interestingly, several adverse effects are less common, compared to BTZ, in patients treated with CFZ. As the molecular details of these observations remain not well understood we assayed the pathophysiological effects of CFZ vs. BTZ in the Drosophila experimental model. Mass Spectrometry analyses showed that neither CFZ nor BTZ are hydrolysed in flies’ tissues, while at doses inducing similar inhibition of the rate limiting for protein breakdown chymotrypsin-like (CT-L) proteasomal activity, CFZ treatment resulted in less intense increase of oxidative stress or activation of antioxidant and proteostatic modules. Also, despite comparable cardiotoxicity likely due to disrupted mitochondrial function, CFZ did not affect developmental processes, showed minimal neuromuscular defects and reduced to a lesser extent flies’ healthspan. Studies in flies, human cancer cell lines and blood cells isolated from Multiple Myeloma patients treated with CFZ or BTZ revealed, that the increased BTZ toxicity likely relates to partial co-inhibition of the caspase-like (C-L) proteasomal activity Supportively, co-treating flies with CFZ and a C-L selective proteasome inhibitor exacerbated CFZ-mediated toxicity. Our findings provide a reasonable explanation for the differential adverse effects of CFZ and BTZ in the clinic.
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spelling pubmed-57365852017-12-21 Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events Tsakiri, Eleni N. Terpos, Evangelos Papanagnou, Eleni-Dimitra Kastritis, Efstathios Brieudes, Vincent Halabalaki, Maria Bagratuni, Tina Florea, Bogdan I. Overkleeft, Herman S. Scorrano, Luca Skaltsounis, Alexios-Leandros Dimopoulos, Meletios A. Trougakos, Ioannis P. Sci Rep Article Proteasome inhibitors, e.g. Bortezomib (BTZ) and Carfilzomib (CFZ), have demonstrated clinical efficacy against haematological cancers. Interestingly, several adverse effects are less common, compared to BTZ, in patients treated with CFZ. As the molecular details of these observations remain not well understood we assayed the pathophysiological effects of CFZ vs. BTZ in the Drosophila experimental model. Mass Spectrometry analyses showed that neither CFZ nor BTZ are hydrolysed in flies’ tissues, while at doses inducing similar inhibition of the rate limiting for protein breakdown chymotrypsin-like (CT-L) proteasomal activity, CFZ treatment resulted in less intense increase of oxidative stress or activation of antioxidant and proteostatic modules. Also, despite comparable cardiotoxicity likely due to disrupted mitochondrial function, CFZ did not affect developmental processes, showed minimal neuromuscular defects and reduced to a lesser extent flies’ healthspan. Studies in flies, human cancer cell lines and blood cells isolated from Multiple Myeloma patients treated with CFZ or BTZ revealed, that the increased BTZ toxicity likely relates to partial co-inhibition of the caspase-like (C-L) proteasomal activity Supportively, co-treating flies with CFZ and a C-L selective proteasome inhibitor exacerbated CFZ-mediated toxicity. Our findings provide a reasonable explanation for the differential adverse effects of CFZ and BTZ in the clinic. Nature Publishing Group UK 2017-12-19 /pmc/articles/PMC5736585/ /pubmed/29259189 http://dx.doi.org/10.1038/s41598-017-17596-4 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Tsakiri, Eleni N.
Terpos, Evangelos
Papanagnou, Eleni-Dimitra
Kastritis, Efstathios
Brieudes, Vincent
Halabalaki, Maria
Bagratuni, Tina
Florea, Bogdan I.
Overkleeft, Herman S.
Scorrano, Luca
Skaltsounis, Alexios-Leandros
Dimopoulos, Meletios A.
Trougakos, Ioannis P.
Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events
title Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events
title_full Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events
title_fullStr Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events
title_full_unstemmed Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events
title_short Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events
title_sort milder degenerative effects of carfilzomib vs. bortezomib in the drosophila model: a link to clinical adverse events
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736585/
https://www.ncbi.nlm.nih.gov/pubmed/29259189
http://dx.doi.org/10.1038/s41598-017-17596-4
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