期刊
JOURNAL OF TRANSLATIONAL MEDICINE
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12967-022-03497-2
关键词
Acute myeloid leukemia; Homoharringtonine; APG-2575; MCL-1; GSK3 beta
资金
- Key international cooperation projects of the National Natural Science Foundation of China [81820108004]
- Natural Science Foundation of China [82170144]
- Ascentage Pharma (Suzhou) Co., Ltd
- Fundamental Research Funds for the Central Universities [WK9110000179]
The combination of APG-2575 and HHT showed synergistic inhibition of AML cell growth and engraftment, providing a potential AML treatment strategy.
Background: 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. Methods: 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. Results: 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/GSK3 beta signaling pathway. Conclusion: Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.
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