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Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas

Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as sel...

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Autores principales: Jeitany, Maya, Prabhu, Aishvaryaa, Dakle, Pushkar, Pathak, Elina, Madan, Vikas, Kanojia, Deepika, Mukundan, Vineeth, Jiang, Yan Yi, Landesman, Yosef, Tam, Wai Leong, Kappei, Dennis, Koeffler, H. Phillip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904719/
https://www.ncbi.nlm.nih.gov/pubmed/32851475
http://dx.doi.org/10.1007/s00018-020-03620-w
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author Jeitany, Maya
Prabhu, Aishvaryaa
Dakle, Pushkar
Pathak, Elina
Madan, Vikas
Kanojia, Deepika
Mukundan, Vineeth
Jiang, Yan Yi
Landesman, Yosef
Tam, Wai Leong
Kappei, Dennis
Koeffler, H. Phillip
author_facet Jeitany, Maya
Prabhu, Aishvaryaa
Dakle, Pushkar
Pathak, Elina
Madan, Vikas
Kanojia, Deepika
Mukundan, Vineeth
Jiang, Yan Yi
Landesman, Yosef
Tam, Wai Leong
Kappei, Dennis
Koeffler, H. Phillip
author_sort Jeitany, Maya
collection PubMed
description Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib’s efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03620-w) contains supplementary material, which is available to authorized users.
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spelling pubmed-79047192021-03-09 Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas Jeitany, Maya Prabhu, Aishvaryaa Dakle, Pushkar Pathak, Elina Madan, Vikas Kanojia, Deepika Mukundan, Vineeth Jiang, Yan Yi Landesman, Yosef Tam, Wai Leong Kappei, Dennis Koeffler, H. Phillip Cell Mol Life Sci Original Article Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib’s efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03620-w) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-08-26 2021 /pmc/articles/PMC7904719/ /pubmed/32851475 http://dx.doi.org/10.1007/s00018-020-03620-w Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article
Jeitany, Maya
Prabhu, Aishvaryaa
Dakle, Pushkar
Pathak, Elina
Madan, Vikas
Kanojia, Deepika
Mukundan, Vineeth
Jiang, Yan Yi
Landesman, Yosef
Tam, Wai Leong
Kappei, Dennis
Koeffler, H. Phillip
Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
title Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
title_full Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
title_fullStr Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
title_full_unstemmed Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
title_short Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
title_sort novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904719/
https://www.ncbi.nlm.nih.gov/pubmed/32851475
http://dx.doi.org/10.1007/s00018-020-03620-w
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