Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Palermo, Italy.
Cancer Lett. 2011 Jan 28;300(2):205-14. doi: 10.1016/j.canlet.2010.10.007. Epub 2010 Oct 30.
Mutation of the Bcr-Abl oncoprotein is one of most frequent mechanisms by which chronic myelogenous leukemia (CML) cells become resistant to imatinib. Here, we show that treatment of cell lines harbouring wild type or mutant BCR-ABL with carboxyamidotriazole (CAI), a calcium influx and signal transduction inhibitor, inhibits cell growth, the expression of Bcr-Abl and its downstream signalling, and induces apoptosis. Moreover, we show that CAI acts by increasing intracellular ROS. Clinically significant, CAI has also inhibitory effects on T315I Bcr-Abl mutant, a mutation that causes CML cells to become insensitive to imatinib and second generation abl kinase inhibitors.
Bcr-Abl 癌蛋白的突变是慢性髓性白血病 (CML) 细胞对伊马替尼产生耐药性的最常见机制之一。在这里，我们表明，用钙内流和信号转导抑制剂羧基三唑（CAI）处理携带野生型或突变 BCR-ABL 的细胞系可抑制细胞生长、Bcr-Abl 的表达及其下游信号转导，并诱导细胞凋亡。此外，我们表明 CAI 通过增加细胞内 ROS 起作用。具有临床意义的是，CAI 对 T315I Bcr-Abl 突变也有抑制作用，该突变导致 CML 细胞对伊马替尼和第二代 abl 激酶抑制剂不敏感。
