Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity...

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Autores principales:	Yi-Hue Kuo, Shih-Hsiang Wei, Jie-Hau Jiang, Yueh-Shih Chang, Mei-Yin Liu, Shu-Ling Fu, Chi-Ying F. Huang, Wey-Jinq Lin
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chronic myeloid leukemia combined therapy imatinib dasatinib p38 MAPK Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/be84e156e6a64ca08f4001dd2d83eb23
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spelling	oai:doaj.org-article:be84e156e6a64ca08f4001dd2d83eb232021-11-25T17:58:00ZPerturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors10.3390/ijms2222125731422-00671661-6596https://doaj.org/article/be84e156e6a64ca08f4001dd2d83eb232021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12573https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5–3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38β, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.Yi-Hue KuoShih-Hsiang WeiJie-Hau JiangYueh-Shih ChangMei-Yin LiuShu-Ling FuChi-Ying F. HuangWey-Jinq LinMDPI AGarticlechronic myeloid leukemiacombined therapyimatinibdasatinibp38 MAPKBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12573, p 12573 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chronic myeloid leukemia combined therapy imatinib dasatinib p38 MAPK Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	chronic myeloid leukemia combined therapy imatinib dasatinib p38 MAPK Biology (General) QH301-705.5 Chemistry QD1-999 Yi-Hue Kuo Shih-Hsiang Wei Jie-Hau Jiang Yueh-Shih Chang Mei-Yin Liu Shu-Ling Fu Chi-Ying F. Huang Wey-Jinq Lin Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors
description	Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5–3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38β, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.
format	article
author	Yi-Hue Kuo Shih-Hsiang Wei Jie-Hau Jiang Yueh-Shih Chang Mei-Yin Liu Shu-Ling Fu Chi-Ying F. Huang Wey-Jinq Lin
author_facet	Yi-Hue Kuo Shih-Hsiang Wei Jie-Hau Jiang Yueh-Shih Chang Mei-Yin Liu Shu-Ling Fu Chi-Ying F. Huang Wey-Jinq Lin
author_sort	Yi-Hue Kuo
title	Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors
title_short	Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors
title_full	Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors
title_fullStr	Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors
title_full_unstemmed	Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors
title_sort	perturbation of p38α mapk as a novel strategy to effectively sensitize chronic myeloid leukemia cells to therapeutic bcr-abl inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/be84e156e6a64ca08f4001dd2d83eb23
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Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors

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