Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality that urgently requires new treatments. ROCK1 plays an essential role in regulating growth and survival in AML cells. In this study, we evaluated GSK269962A, a selective ROCK1 inhibitor, in preclinical models of...
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| Format: | Article |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1064470/full |
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| author | Ting Pan Ting Pan Sijia Wang Sijia Wang Hao Feng Hao Feng Jiawen Xu Jiawen Xu Miao Zhang Miao Zhang Yao Yao Yao Yao Kailin Xu Kailin Xu Mingshan Niu Mingshan Niu |
| author_facet | Ting Pan Ting Pan Sijia Wang Sijia Wang Hao Feng Hao Feng Jiawen Xu Jiawen Xu Miao Zhang Miao Zhang Yao Yao Yao Yao Kailin Xu Kailin Xu Mingshan Niu Mingshan Niu |
| author_sort | Ting Pan |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality that urgently requires new treatments. ROCK1 plays an essential role in regulating growth and survival in AML cells. In this study, we evaluated GSK269962A, a selective ROCK1 inhibitor, in preclinical models of AML. Compared with solid tumors, GSK269962A selectively inhibited cell growth and clonogenicity of AML cells. Furthermore, GSK269962A arrested AML cells in the G2 phase and induced apoptosis by regulating multiple cell cycle- and apoptosis-associated proteins. Strikingly, GSK269962A could eliminate leukemia cells from bone marrow, liver, and spleen in an animal model of AML and significantly prolong mouse survival. Mechanistically, GSK269962A could inhibit the growth of AML by blocking ROCK1/c-Raf/ERK signaling pathway. Notably, a correlation was found between the expression levels of ROCK1 protein and the sensitivity of GSK269962A in AML. These data highlight the potential role of ROCK1 as an attractive target for treating AML, as well as the potential of GSK269962A for use in clinical trials of AML. |
| first_indexed | 2024-04-11T13:35:47Z |
| format | Article |
| id | doaj.art-b3df557efa5d45a4ada7ab54a73b042d |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T13:35:47Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-b3df557efa5d45a4ada7ab54a73b042d2022-12-22T04:21:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.10644701064470Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemiaTing Pan0Ting Pan1Sijia Wang2Sijia Wang3Hao Feng4Hao Feng5Jiawen Xu6Jiawen Xu7Miao Zhang8Miao Zhang9Yao Yao10Yao Yao11Kailin Xu12Kailin Xu13Mingshan Niu14Mingshan Niu15Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaAcute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality that urgently requires new treatments. ROCK1 plays an essential role in regulating growth and survival in AML cells. In this study, we evaluated GSK269962A, a selective ROCK1 inhibitor, in preclinical models of AML. Compared with solid tumors, GSK269962A selectively inhibited cell growth and clonogenicity of AML cells. Furthermore, GSK269962A arrested AML cells in the G2 phase and induced apoptosis by regulating multiple cell cycle- and apoptosis-associated proteins. Strikingly, GSK269962A could eliminate leukemia cells from bone marrow, liver, and spleen in an animal model of AML and significantly prolong mouse survival. Mechanistically, GSK269962A could inhibit the growth of AML by blocking ROCK1/c-Raf/ERK signaling pathway. Notably, a correlation was found between the expression levels of ROCK1 protein and the sensitivity of GSK269962A in AML. These data highlight the potential role of ROCK1 as an attractive target for treating AML, as well as the potential of GSK269962A for use in clinical trials of AML.https://www.frontiersin.org/articles/10.3389/fphar.2022.1064470/fullacute myeloid leukemiatargeted therapyROCK1GSK269962AERK |
| spellingShingle | Ting Pan Ting Pan Sijia Wang Sijia Wang Hao Feng Hao Feng Jiawen Xu Jiawen Xu Miao Zhang Miao Zhang Yao Yao Yao Yao Kailin Xu Kailin Xu Mingshan Niu Mingshan Niu Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia Frontiers in Pharmacology acute myeloid leukemia targeted therapy ROCK1 GSK269962A ERK |
| title | Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia |
| title_full | Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia |
| title_fullStr | Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia |
| title_full_unstemmed | Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia |
| title_short | Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia |
| title_sort | preclinical evaluation of the rock1 inhibitor gsk269962a in acute myeloid leukemia |
| topic | acute myeloid leukemia targeted therapy ROCK1 GSK269962A ERK |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1064470/full |
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