Neoplasma Vol.70, No.2, p. 287–293, 2023
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| Title: Synergistic activity and mechanism of cytarabine and MCL-1 inhibitor AZD5991 against acute myeloid leukemia |
| Author: Yue Wang, Deying Wang, Yao Wang, Haotian Yang, Guan Wang, Shuangshuang Wu |
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Abstract: The 5-year overall survival rate of acute myeloid leukemia (AML) is less than 30%. Improving clinical outcomes is still a clinical challenge for AML treatment. Simultaneous use of chemotherapeutic drugs and targeting of apoptosis pathways has become a first-line clinical treatment for AML. Myeloid cell leukemia 1 (MCL-1) is a candidate target for AML treatment. In this study, we demonstrated that inhibition of the anti-apoptotic protein MCL-1 by AZD5991 synergistic increased chemotherapeutic agent cytarabine (Ara-C)-induced apoptosis in AML cell lines and primary patient samples. Apoptosis induced by a combination of Ara-C and AZD5991 was partially dependent on caspase activity and Bak/Bax. The downregulation of MCL-1 by Ara-C and the enhancement of Ara-C-induced DNA damage through inhibition of MCL-1 are potential mechanisms underlying the synergistic anti-AML activity between Ara-C and AZD5991. Our data support the application of MCL-1 inhibitor in combination with the conventional chemotherapeutic agent for the clinical treatment of AML.
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| Keywords: acute myeloid leukemia; combination treatment; MCL-1; apoptosis; DNA damage |
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Published online: 22-Feb-2023
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| Year: 2023, Volume: 70, Issue: 2 |
Page From: 287, Page To: 293 |
doi:10.4149/neo_2023_221217N1185
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