Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Science, Hemmat Highway, 1449614535, Tehran, Iran.
Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Mol Biol Rep. 2022 Mar;49(3):2025-2036. doi: 10.1007/s11033-021-07021-5. Epub 2022 Feb 9.
Myeloid cell leukemia-1 (MCL-1) is a component of the Bcl-2 anti-apoptotic family that plays a key role in cell proliferation and differentiation. Despite tremendous improvements toward identification of the role of MCL-1 in leukemia progression, the functional significance and molecular mechanism behind the effect of MCL-1 overexpression on the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has not been clarified. In addition, less well appreciated is the effect of MCL-1 inhibition on the potentiation of doxorubicin-induced apoptosis in BCP-ALL cell lines. In the present study, we aimed to shed light on the anti-cancer properties of S63845, a potent Mcl-1 inhibitor, in BCP-ALL cell lines either alone or in combination with a chemotherapeutic drug. METHODS AND RESULTS: Mononuclear cells from patients with Pre-B ALL and BCP-ALL cell lines were treated with S63845 in presence or absence of doxorubicin, induction of apoptosis was evaluated using Annexin-V/PI staining kit. mRNA and protein expression levels were assessed by qRT-PCR and western blot analysis, respectively. Our results declared that inhibition of Mcl-1 impairs cell growth and induces apoptosis in pre-B ALL cells through activation of caspase-3 and up-regulation of a repertoire of pro-apoptotic Bcl-2 family. Additionally, S63845 acts synergically with doxorubicin to induce apoptosis in BCP-ALL cell lines.
Our data declared that MCL-1 inhibition alone or in combination with a chemotherapeutic agent is considered an appealing strategy for the induction of apoptosis in BCP-ALL cells.
髓样细胞白血病-1（MCL-1）是 Bcl-2 抗凋亡家族的一个组成部分，在细胞增殖和分化中起着关键作用。尽管在确定 MCL-1 在白血病进展中的作用方面取得了巨大进展，但 MCL-1 过表达对前 B 细胞急性淋巴细胞白血病（BCP-ALL）细胞增殖的影响的功能意义和分子机制尚未阐明。此外，人们对 MCL-1 抑制对增强 BCP-ALL 细胞系中阿霉素诱导的细胞凋亡的影响认识不足。在本研究中，我们旨在阐明强效 MCL-1 抑制剂 S63845 在 BCP-ALL 细胞系中单独或与化疗药物联合使用的抗癌特性。
用 S63845 处理 Pre-B ALL 患者的单核细胞和 BCP-ALL 细胞系，在存在或不存在阿霉素的情况下，用 Annexin-V/PI 染色试剂盒评估细胞凋亡的诱导。通过 qRT-PCR 和 Western blot 分析分别评估 mRNA 和蛋白表达水平。我们的结果表明，通过激活 caspase-3 和上调一系列促凋亡 Bcl-2 家族成员，抑制 Mcl-1 可损害 Pre-B ALL 细胞的生长并诱导其凋亡。此外，S63845 与阿霉素协同作用诱导 BCP-ALL 细胞系发生细胞凋亡。
我们的数据表明，MCL-1 抑制单独或与化疗药物联合使用是诱导 BCP-ALL 细胞凋亡的一种有吸引力的策略。
