Synergistic activity and mechanism of cytarabine and MCL-1 inhibitor AZD5991 against acute myeloid leukemia.

IF 2 4区医学 Q3 ONCOLOGY

Neoplasma Pub Date : 2023-04-01 DOI:10.4149/neo_2023_221217N1185

Yue Wang, Deying Wang, Yao Wang, Haotian Yang, Guan Wang, Shuangshuang Wu

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引用次数: 2

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 synergistically 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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阿糖胞苷与MCL-1抑制剂AZD5991对急性髓系白血病的协同作用及机制

急性髓性白血病(AML)的5年总生存率低于30%。改善临床结果仍然是AML治疗的临床挑战。同时使用化疗药物和靶向细胞凋亡途径已成为AML的一线临床治疗方法。髓细胞白血病1 (MCL-1)是AML治疗的候选靶点。在这项研究中，我们证明AZD5991抑制抗凋亡蛋白MCL-1协同增加化疗药物阿糖胞苷(Ara-C)诱导的AML细胞系和原发患者样本的凋亡。Ara-C和AZD5991联合诱导的细胞凋亡部分依赖于caspase活性和Bak/Bax。Ara-C对MCL-1的下调以及通过抑制MCL-1而增强其诱导的DNA损伤是Ara-C和AZD5991之间协同抗aml活性的潜在机制。我们的数据支持MCL-1抑制剂与常规化疗药物联合应用于AML的临床治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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