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

Abstract 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 pharmacothera...

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Autores principales:	Jacob W. Greenberg, Hogyoung Kim, Ahmed A. Moustafa, Amrita Datta, Pedro C. Barata, A. Hamid Boulares, Asim B. Abdel-Mageed, Louis S. Krane
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8bcce53528064b139c18bf1570a9c148
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spelling	oai:doaj.org-article:8bcce53528064b139c18bf1570a9c1482021-12-02T15:42:59ZRepurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma10.1038/s41598-021-89655-w2045-2322https://doaj.org/article/8bcce53528064b139c18bf1570a9c1482021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89655-whttps://doaj.org/toc/2045-2322Abstract 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.Jacob W. GreenbergHogyoung KimAhmed A. MoustafaAmrita DattaPedro C. BarataA. Hamid BoularesAsim B. Abdel-MageedLouis S. KraneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jacob W. Greenberg Hogyoung Kim Ahmed A. Moustafa Amrita Datta Pedro C. Barata A. Hamid Boulares Asim B. Abdel-Mageed Louis S. Krane Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
description	Abstract 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.
format	article
author	Jacob W. Greenberg Hogyoung Kim Ahmed A. Moustafa Amrita Datta Pedro C. Barata A. Hamid Boulares Asim B. Abdel-Mageed Louis S. Krane
author_facet	Jacob W. Greenberg Hogyoung Kim Ahmed A. Moustafa Amrita Datta Pedro C. Barata A. Hamid Boulares Asim B. Abdel-Mageed Louis S. Krane
author_sort	Jacob W. Greenberg
title	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_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_sort	repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8bcce53528064b139c18bf1570a9c148
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Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma

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