Zhao Yin, Ya Gao, Xiaoyin Bu, Junhui Wang, Zurong Yao, Qifa Liu, Yu Zhang, Guopan Yu, Baohong Ping
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引用次数: 0
摘要
Venetoclax(VEN)是一种B细胞淋巴瘤2(BCL-2)选择性抑制剂,被广泛用于治疗急性髓性白血病(AML),并取得了良好的疗效。然而,VEN在复发/难治性(R/R)AML中的抗白血病效果有待改善。在这项研究中,我们观察到,在复发性/难治性急性髓细胞白血病(R/R-AML)患者中,将同型半胱氨酸(HHT)与 VEN 加上阿扎胞苷联合使用,比单独使用 VA 的反应明显更强,生存率更高。基础研究表明,HHT 联合 VEN 对体内耐药急性髓细胞白血病细胞和间充质干细胞(MSC)共培养/不共培养的原代细胞均有高度协同作用,可抑制急性髓细胞白血病细胞的增殖和集落形成能力,同时抑制细胞周期停滞。从机理上讲,HHT通过下调抗凋亡蛋白MCL-1/BCL-xL、激活活性氧(ROS)导致线粒体膜电位丧失和减少脂肪酸(FA)摄取,使AML细胞对VEN敏感。这些研究结果表明,在基于 VEN 的治疗方案中加入 HHT 可提高 R/R-AML 患者的治疗效果。
Homoharringtonine sensitized resistant acute myeloid leukemia cells to venetoclax-induced apoptosis.
Venetoclax (VEN), a B-cell lymphoma 2 (BCL-2) selective inhibitor, is widely used for treating acute myeloid leukemia (AML) with promising results. However, the anti-leukemic effect of VEN in relapsed/refractory (R/R)- AML requires improvement. In this study, we observed that combining homoharringtonine (HHT) with VEN plus azacitidine resulted in a significantly higher response and better survival than VA alone in patients with R/R-AML. Basic research indicates that HHT combined with VEN has a highly synergistic effect against both resistant AML cells and primary cells with/without mesenchymal stem cell (MSC) co-culture in vivo, inhibiting proliferation and colony-forming capacity of AML cells associated with concomitant cell cycle arrest. Mechanistically, HHT sensitizes AML cells to VEN by downregulating the anti-apoptotic proteins MCL-1/BCL-xL, activating reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and attenuating fatty acid (FA) uptake. These findings adding HHT to VEN-based regimens may enhance outcomes in R/R-AML patients.
期刊介绍:
Leukemia & Lymphoma in its fourth decade continues to provide an international forum for publication of high quality clinical, translational, and basic science research, and original observations relating to all aspects of hematological malignancies. The scope ranges from clinical and clinico-pathological investigations to fundamental research in disease biology, mechanisms of action of novel agents, development of combination chemotherapy, pharmacology and pharmacogenomics as well as ethics and epidemiology. Submissions of unique clinical observations or confirmatory studies are considered and published as Letters to the Editor