Cargando…

Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was develo...

Descripción completa

Detalles Bibliográficos
Autores principales: Heo, Sook-Kyoung, Noh, Eui-Kyu, Yu, Ho-Min, Kim, Do Kyoung, Seo, Hye Jin, Lee, Yoo Jin, Cheon, Jaekyung, Koh, Su Jin, Min, Young Joo, Choi, Yunsuk, Jo, Jae-Cheol
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718665/
https://www.ncbi.nlm.nih.gov/pubmed/33276759
http://dx.doi.org/10.1186/s12885-020-07701-8
_version_ 1783619535229681664
author Heo, Sook-Kyoung
Noh, Eui-Kyu
Yu, Ho-Min
Kim, Do Kyoung
Seo, Hye Jin
Lee, Yoo Jin
Cheon, Jaekyung
Koh, Su Jin
Min, Young Joo
Choi, Yunsuk
Jo, Jae-Cheol
author_facet Heo, Sook-Kyoung
Noh, Eui-Kyu
Yu, Ho-Min
Kim, Do Kyoung
Seo, Hye Jin
Lee, Yoo Jin
Cheon, Jaekyung
Koh, Su Jin
Min, Young Joo
Choi, Yunsuk
Jo, Jae-Cheol
author_sort Heo, Sook-Kyoung
collection PubMed
description BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study. METHODS: Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. RESULTS: The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G(0)/G(1) arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G(0)/G(1) arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. CONCLUSIONS: Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-020-07701-8.
format Online
Article
Text
id pubmed-7718665
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-77186652020-12-07 Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death Heo, Sook-Kyoung Noh, Eui-Kyu Yu, Ho-Min Kim, Do Kyoung Seo, Hye Jin Lee, Yoo Jin Cheon, Jaekyung Koh, Su Jin Min, Young Joo Choi, Yunsuk Jo, Jae-Cheol BMC Cancer Research Article BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study. METHODS: Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. RESULTS: The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G(0)/G(1) arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G(0)/G(1) arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. CONCLUSIONS: Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-020-07701-8. BioMed Central 2020-12-04 /pmc/articles/PMC7718665/ /pubmed/33276759 http://dx.doi.org/10.1186/s12885-020-07701-8 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Heo, Sook-Kyoung
Noh, Eui-Kyu
Yu, Ho-Min
Kim, Do Kyoung
Seo, Hye Jin
Lee, Yoo Jin
Cheon, Jaekyung
Koh, Su Jin
Min, Young Joo
Choi, Yunsuk
Jo, Jae-Cheol
Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death
title Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death
title_full Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death
title_fullStr Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death
title_full_unstemmed Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death
title_short Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death
title_sort radotinib enhances cytarabine (ara-c)-induced acute myeloid leukemia cell death
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718665/
https://www.ncbi.nlm.nih.gov/pubmed/33276759
http://dx.doi.org/10.1186/s12885-020-07701-8
work_keys_str_mv AT heosookkyoung radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT noheuikyu radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT yuhomin radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT kimdokyoung radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT seohyejin radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT leeyoojin radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT cheonjaekyung radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT kohsujin radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT minyoungjoo radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT choiyunsuk radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath
AT jojaecheol radotinibenhancescytarabinearacinducedacutemyeloidleukemiacelldeath