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Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma

Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exoso...

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Autores principales: Greenberg, Jacob W., Kim, Hogyoung, Moustafa, Ahmed A., Datta, Amrita, Barata, Pedro C., Boulares, A. Hamid, Abdel-Mageed, Asim B., Krane, Louis S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119955/
https://www.ncbi.nlm.nih.gov/pubmed/33986386
http://dx.doi.org/10.1038/s41598-021-89655-w
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author Greenberg, Jacob W.
Kim, Hogyoung
Moustafa, Ahmed A.
Datta, Amrita
Barata, Pedro C.
Boulares, A. Hamid
Abdel-Mageed, Asim B.
Krane, Louis S.
author_facet Greenberg, Jacob W.
Kim, Hogyoung
Moustafa, Ahmed A.
Datta, Amrita
Barata, Pedro C.
Boulares, A. Hamid
Abdel-Mageed, Asim B.
Krane, Louis S.
author_sort Greenberg, Jacob W.
collection PubMed
description Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ’s inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.
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spelling pubmed-81199552021-05-17 Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma Greenberg, Jacob W. Kim, Hogyoung Moustafa, Ahmed A. Datta, Amrita Barata, Pedro C. Boulares, A. Hamid Abdel-Mageed, Asim B. Krane, Louis S. Sci Rep Article Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ’s inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies. Nature Publishing Group UK 2021-05-13 /pmc/articles/PMC8119955/ /pubmed/33986386 http://dx.doi.org/10.1038/s41598-021-89655-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Greenberg, Jacob W.
Kim, Hogyoung
Moustafa, Ahmed A.
Datta, Amrita
Barata, Pedro C.
Boulares, A. Hamid
Abdel-Mageed, Asim B.
Krane, Louis S.
Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
title Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
title_full Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
title_fullStr Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
title_full_unstemmed Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
title_short Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
title_sort repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119955/
https://www.ncbi.nlm.nih.gov/pubmed/33986386
http://dx.doi.org/10.1038/s41598-021-89655-w
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