Konopleva Marina, Contractor Rooha, Tsao Twee, Samudio Ismael, Ruvolo Peter P, Kitada Shinichi, Deng Xingming, Zhai Dayong, Shi Yue-Xi, Sneed Thomas, Verhaegen Monique, Soengas Maria, Ruvolo Vivian R, McQueen Teresa, Schober Wendy D, Watt Julie C, Jiffar Tilahun, Ling Xiaoyang, Marini Frank C, Harris David, Dietrich Martin, Estrov Zeev, McCubrey James, May W Stratford, Reed John C, Andreeff Michael
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.
BCL-2蛋白对细胞存活至关重要，且在许多肿瘤中过表达。ABT-737是一种小分子BH3模拟物，在临床前研究中对淋巴瘤和小细胞肺癌具有单药活性。我们在此报告，ABT-737可有效杀死急性髓性白血病母细胞、祖细胞和干细胞，而不影响正常造血细胞。ABT-737诱导BCL-2/BAX复合物的破坏以及内源性凋亡途径的BAK依赖性但BIM非依赖性激活。在具有磷酸化BCL-2或MCL-1增加的细胞中，ABT-737无活性。抑制BCL-2磷酸化和降低MCL-1表达可恢复对ABT-737的敏感性。这些数据表明，当考虑到此处确定的耐药机制时，ABT-737可能是一种高效的抗白血病药物。
