| Autor: |
Qiang Qiu, Linyu yang, Yunyu Feng, Zejiang Zhu, Ning Li, Li Zheng, Yuanyuan Sun, Cong Pan, Huandi Qiu, Xue Cui, Wei He, Fang Wang, Yuyao Yi, Minghai Tang, Zhuang Yang, Yunfan Yang, Zhihui Li, Lijuan Chen, Yiguo Hu |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Bioactive Materials, Vol 21, Iss , Pp 483-498 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2452-199X |
| DOI: |
10.1016/j.bioactmat.2022.08.006 |
| Popis: |
Purinostat Mesylate (PM) is a novel highly selective and active HDAC I/IIb inhibitor, and the injectable formulation of PM (PMF) based on the compound prescription containing cyclodextrin completely can overcome PM's poor solubility and improves its stability and pharmacokinetic properties. Here, we showed that PM effectively repressed the survival of Ph+ leukemia cells and CD34+ leukemia cells from CML patients in vitro. In vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I) induced CML progression by restraining leukemia stem cells (LSCs), which are insensitive to chemotherapy and responsible for CML relapse. Mechanism studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc, β-Catenin, E2f, Ezh2, Alox5, and mTOR, as well as interrupted some critical biologic processes. Additionally, PMF increased glutamate metabolism in LSCs by increasing GLS1. The combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and self-renewal. Overall, our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis, which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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