The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway

Abstract Multiple myeloma (MM) is a hematological cancer resulting from accumulated abnormal plasma cells. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, curren...

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Autores principales:	Sook-Kyoung Heo, Eui-Kyu Noh, Jeong Yi Kim, Ho-Min Yu, Jun Young Sung, Lan Jeong Ju, Do Kyoung Kim, Hye Jin Seo, Yoo Jin Lee, Jaekyung Cheon, SuJin Koh, Young Joo Min, Yunsuk Choi, Jae-Cheol Jo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/43d427a0131f4e40b71f116b3d316acb
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spelling	oai:doaj.org-article:43d427a0131f4e40b71f116b3d316acb2021-12-02T17:12:17ZThe c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway10.1038/s41598-021-92651-92045-2322https://doaj.org/article/43d427a0131f4e40b71f116b3d316acb2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92651-9https://doaj.org/toc/2045-2322Abstract Multiple myeloma (MM) is a hematological cancer resulting from accumulated abnormal plasma cells. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and the platelet-derived growth factor receptor. Generally, the mechanism of inhibition of non-receptor tyrosine kinase c-Abl has played an essential role in the inhibition of cancer progression. However, little is known regarding the effects of the c-Abl inhibitor, radotinib on MM cells. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Interestingly, radotinib caused apoptosis in MM cells including RPMI-8226, MM.1S, and IM-9 cells, even in the absence of c-kit expression in 2 of these lines. Radotinib treatment significantly increased the number Annexin V-positive cells and decreased the mitochondrial membrane potential in MM cells. Additionally, we observed that cytochrome C was localized in the cytosol of radotinib-treated MM cells. Moreover, radotinib decreased the expression of Bcl-2 and Bcl-xL, and increased the expression of Bax and Bak in MM cells. Furthermore, radotinib promoted caspase pathway activation by inducing the expression and activity of caspase-3, -7, and -9. Expression of cleaved PARP-1 was also increased by radotinib treatment in various MM cells. In addition, radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells, and killed ex vivo myeloma cells from patients. In conclusion, radotinib may play an important role as a candidate agent or chemosensitizer for the treatment of MM.Sook-Kyoung HeoEui-Kyu NohJeong Yi KimHo-Min YuJun Young SungLan Jeong JuDo Kyoung KimHye Jin SeoYoo Jin LeeJaekyung CheonSuJin KohYoung Joo MinYunsuk ChoiJae-Cheol JoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sook-Kyoung Heo Eui-Kyu Noh Jeong Yi Kim Ho-Min Yu Jun Young Sung Lan Jeong Ju Do Kyoung Kim Hye Jin Seo Yoo Jin Lee Jaekyung Cheon SuJin Koh Young Joo Min Yunsuk Choi Jae-Cheol Jo The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway
description	Abstract Multiple myeloma (MM) is a hematological cancer resulting from accumulated abnormal plasma cells. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and the platelet-derived growth factor receptor. Generally, the mechanism of inhibition of non-receptor tyrosine kinase c-Abl has played an essential role in the inhibition of cancer progression. However, little is known regarding the effects of the c-Abl inhibitor, radotinib on MM cells. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Interestingly, radotinib caused apoptosis in MM cells including RPMI-8226, MM.1S, and IM-9 cells, even in the absence of c-kit expression in 2 of these lines. Radotinib treatment significantly increased the number Annexin V-positive cells and decreased the mitochondrial membrane potential in MM cells. Additionally, we observed that cytochrome C was localized in the cytosol of radotinib-treated MM cells. Moreover, radotinib decreased the expression of Bcl-2 and Bcl-xL, and increased the expression of Bax and Bak in MM cells. Furthermore, radotinib promoted caspase pathway activation by inducing the expression and activity of caspase-3, -7, and -9. Expression of cleaved PARP-1 was also increased by radotinib treatment in various MM cells. In addition, radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells, and killed ex vivo myeloma cells from patients. In conclusion, radotinib may play an important role as a candidate agent or chemosensitizer for the treatment of MM.
format	article
author	Sook-Kyoung Heo Eui-Kyu Noh Jeong Yi Kim Ho-Min Yu Jun Young Sung Lan Jeong Ju Do Kyoung Kim Hye Jin Seo Yoo Jin Lee Jaekyung Cheon SuJin Koh Young Joo Min Yunsuk Choi Jae-Cheol Jo
author_facet	Sook-Kyoung Heo Eui-Kyu Noh Jeong Yi Kim Ho-Min Yu Jun Young Sung Lan Jeong Ju Do Kyoung Kim Hye Jin Seo Yoo Jin Lee Jaekyung Cheon SuJin Koh Young Joo Min Yunsuk Choi Jae-Cheol Jo
author_sort	Sook-Kyoung Heo
title	The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway
title_short	The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway
title_full	The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway
title_fullStr	The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway
title_full_unstemmed	The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway
title_sort	c-abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/43d427a0131f4e40b71f116b3d316acb
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The c-Abl inhibitor, radotinib induces apoptosis in multiple myeloma cells via mitochondrial-dependent pathway

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