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- Title
Homoharringtonine is synergistically lethal with BCL-2 inhibitor APG-2575 in acute myeloid leukemia.
- Authors
Wei, Wenwen; Huang, Shujuan; Ling, Qing; Mao, Shihui; Qian, Yu; Ye, Wenle; Li, Fenglin; Pan, Jiajia; Lin, Xiangjie; Huang, Jiansong; Huang, Xin; Zhai, Yifan; Sun, Jie; Jin, Jie
- Abstract
<bold>Background: </bold>Despite advances in targeted agent development, effective treatment of acute myeloid leukemia (AML) remains a major clinical challenge. The B-cell lymphoma-2 (BCL-2) inhibitor exhibited promising clinical activity in AML, acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) treatment. APG-2575 is a novel BCL-2 selective inhibitor, which has demonstrated anti-tumor activity in hematologic malignancies. Homoharringtonine (HHT), an alkaloid, exhibited anti-AML activity.<bold>Methods: </bold>The synergistic effects of APG-2575 and HHT were studied in AML cell lines and primary samples. MTS was used to measure the cell viability. Annexin V/propidium iodide staining was used to measure the apoptosis rate by flow cytometry. AML cell xenografted mouse models were established to evaluate the anti-leukemic effect of BCL-2 inhibitor, HHT and their combination in vivo. Western blot was used to determine the expression of related proteins.<bold>Results: </bold>APG-2575 showed comparable anti-leukemic effect to the FDA-approved BCL-2 inhibitor ABT-199 in vitro and in vivo. Combined treatment of HHT with APG-2575 synergistically inhibited AML cell growth and engraftment. Mechanistically, HHT promoted degradation of myeloid cell leukemia-1 (MCL-1), which was reported to induce BCL-2 inhibitor resistant, through the PI3K/AKT/GSK3β signaling pathway.<bold>Conclusion: </bold>Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.
- Subjects
THERAPEUTIC use of antineoplastic agents; PROTEINS; PHOSPHOTRANSFERASES; RESEARCH funding; CELL lines; MICE; ANIMALS
- Publication
Journal of Translational Medicine, 2022, Vol 20, Issue 1, p1
- ISSN
1479-5876
- Publication type
journal article
- DOI
10.1186/s12967-022-03497-2