Xie Chengzhi, Edwards Holly, Caldwell J Timothy, Wang Guan, Taub Jeffrey W, Ge Yubin
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China.
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
Mol Oncol. 2015 Feb;9(2):409-21. doi: 10.1016/j.molonc.2014.09.008. Epub 2014 Oct 2.
Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl-2, Bcl-xL, and/or Mcl-1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti-apoptotic Bcl-2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan-Bcl-2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double-strand breaks (DSBs) preceded a decrease of Mcl-1 levels, nuclear translocation of Bcl-2, Bcl-xL, and Mcl-1, and apoptosis. These results indicate that obatoclax enhances cytarabine-induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA-damaging agents in AML and possibly a broader range of malignancies.
对基于阿糖胞苷和蒽环类药物的化疗产生耐药性是急性髓系白血病（AML）患者治疗失败的主要原因。Bcl-2、Bcl-xL和/或Mcl-1的过表达与AML细胞系中的化疗耐药以及AML患者的不良临床预后相关。因此，抗凋亡Bcl-2家族蛋白抑制剂可能是新型治疗药物。在本研究中，我们调查了临床上可达到的浓度的泛Bcl-2抑制剂奥巴托克斯如何增强阿糖胞苷在AML细胞中的抗白血病活性。AML细胞系和诊断性原始细胞的MTT试验以及AML细胞系的流式细胞术分析显示阿糖胞苷和奥巴托克斯之间具有协同抗白血病活性。在联合用药而非单独用药处理中检测到Bax激活。这伴随着线粒体膜电位的显著丧失增加。最重要的是，在用联合药物处理的AML细胞中，DNA双链断裂（DSB）的早期诱导增强先于Mcl-1水平降低、Bcl-2、Bcl-xL和Mcl-1的核转位以及细胞凋亡。这些结果表明奥巴托克斯通过增强DNA DSB来增强阿糖胞苷诱导的细胞凋亡。这种新机制为BH3模拟物与DNA损伤剂联合用于AML以及可能更广泛的恶性肿瘤的临床应用提供了有力证据。
