{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T13:25:58Z","timestamp":1782912358186,"version":"3.54.5"},"reference-count":38,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T00:00:00Z","timestamp":1637539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology and Chang Gung medical research fund","award":["MOST 108-2320-B-010-017 and grant No: MOST 110-2320-B-A49A-541 -  and grant No: CMRPG2F0231."],"award-info":[{"award-number":["MOST 108-2320-B-010-017 and grant No: MOST 110-2320-B-A49A-541 -  and grant No: CMRPG2F0231."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 p38\u03b1 greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5\u20133.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38\u03b2, which displays the most sequence similarity to p38\u03b1, 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 p38\u03b1 inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38\u03b1 deficiency in future clinic application. Taken together, our results demonstrated that p38\u03b1 is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.<\/jats:p>","DOI":"10.3390\/ijms222212573","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T02:46:08Z","timestamp":1637721968000},"page":"12573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Perturbation of p38\u03b1 MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors"],"prefix":"10.3390","volume":"22","author":[{"given":"Yi-Hue","family":"Kuo","sequence":"first","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hsiang","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie-Hau","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5182-7911","authenticated-orcid":false,"given":"Yueh-Shih","family":"Chang","sequence":"additional","affiliation":[{"name":"Hemato-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Keelung & Chang Gung University, Taoyuan City 33302, Taiwan"},{"name":"Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Yin","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ling","family":"Fu","sequence":"additional","affiliation":[{"name":"Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ying F.","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"},{"name":"Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2169-8298","authenticated-orcid":false,"given":"Wey-Jinq","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.2174\/157436206775269181","article-title":"Design and development of signal transduction inhibitors for cancer treatment: Experience and challenges with kinase targets","volume":"1","author":"Ian","year":"2006","journal-title":"Curr. 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