Kuroda Junya, Kimura Shinya, Andreeff Michael, Ashihara Eishi, Kamitsuji Yuri, Yokota Asumi, Kawata Eri, Takeuchi Miki, Tanaka Ruriko, Murotani Yoshihide, Matsumoto Yosuke, Tanaka Hideo, Strasser Andreas, Taniwaki Masafumi, Maekawa Taira
Division of Haematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
Br J Haematol. 2008 Jan;140(2):181-90. doi: 10.1111/j.1365-2141.2007.06899.x. Epub 2007 Nov 20.
The effect of ABT-737, a BH3-mimicking inhibitor for anti-apoptotic Bcl-2 and Bcl-X(L), but not Mcl-1, against Bcr-Abl-positive (Bcr-Abl(+)) leukaemic cells was examined. ABT-737 potently induced apoptosis in Bcr-Abl(+) chronic myeloid leukaemia (CML) cell lines and primary CML samples in vitro and prolonged the survival of mice xenografted with BV173 cells, a CML cell line. Higher expression of anti-apoptotic Bcl-2 proteins reduced cell killing by ABT-737 in each cell line, but there was no correlation between the sensitivities to ABT-737 and the specific expression patterns of Bcl-2 family proteins among cell lines. Thus, the cell killing effect of ABT-737 must be determined not only by the expression patterns of Bcl-2 family proteins but also by other mechanisms, such as high expression of Bcr-Abl, or a drug-efflux pump, in CML cells. ABT-737 augmented the cell killing effect of imatinib in Bcr-Abl(+) cells with diverse drug-resistance mechanisms unless leukaemic cells harboured imatinib-insensitive Abl kinase domain mutations, such as T315I. The combination of homoharringtonine that reduces Mcl-1 enhanced the killing by ABT-737 strongly in Bcr-Abl(+) cells even with T315I mutation. These results suggest that ABT-737 is a useful component of chemotherapies for CML with diverse drug-resistance mechanisms.
研究了ABT - 737（一种针对抗凋亡蛋白Bcl - 2和Bcl - X(L)而非Mcl - 1的BH3模拟抑制剂）对Bcr - Abl阳性（Bcr - Abl(+)）白血病细胞的作用。ABT - 737在体外能有效诱导Bcr - Abl(+)慢性粒细胞白血病（CML）细胞系和原发性CML样本发生凋亡，并延长了接种CML细胞系BV173细胞的小鼠的生存期。抗凋亡Bcl - 2蛋白的高表达降低了ABT - 737对每个细胞系的细胞杀伤作用，但细胞系对ABT - 737的敏感性与Bcl - 2家族蛋白的特定表达模式之间没有相关性。因此，ABT - 737的细胞杀伤作用不仅取决于Bcl - 2家族蛋白的表达模式，还取决于其他机制，如CML细胞中Bcr - Abl的高表达或药物外排泵。ABT - 737增强了伊马替尼对具有多种耐药机制的Bcr - Abl(+)细胞的细胞杀伤作用，除非白血病细胞携带伊马替尼不敏感的Abl激酶结构域突变，如T315I。降低Mcl - 1的高三尖杉酯碱与ABT - 737联合使用，即使对具有T315I突变的Bcr - Abl(+)细胞也能强烈增强杀伤作用。这些结果表明，ABT - 737是用于治疗具有多种耐药机制的CML化疗的有用成分。
