Jia Hong-Yun, Wu Jiang-Xue, Zhu Xiao-Feng, Chen Jie-Min, Yang Shi-Ping, Yan Hai-Jiao, Tan Li, Zeng Yi-Xin, Huang Wenlin
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China.
Leuk Res. 2009 Nov;33(11):1512-9. doi: 10.1016/j.leukres.2009.03.033. Epub 2009 Apr 25.
ZD6474 is an orally available, small-molecule tyrosine kinase inhibitor. This study explores the effect of ZD6474 on imatinib-resistant K562 cell lines, which show markedly increased SRC family kinases (SFKs) activity. ZD6474 induces growth arrest and apoptosis of imatinib-resistant and parental K562 cells, as well as inhibition of Src activity and its downstream effectors, the anti-apoptotic Bcl-2 family. ZD6474 treatment also inhibits the activity of STAT3 and reactivation of its activity results in suppression of the anti-tumor effects of SFKs inhibitors. A single oral administration of ZD6474 produced dose-dependent inhibition of imatinib-resistant K562 cells xenograft tumors. These results suggest that clinical assessment of ZD6474 against imatinib-resistant CML is warranted.
ZD6474是一种口服可用的小分子酪氨酸激酶抑制剂。本研究探讨了ZD6474对伊马替尼耐药的K562细胞系的作用，这些细胞系显示SRC家族激酶（SFKs）活性显著增加。ZD6474可诱导伊马替尼耐药和亲本K562细胞的生长停滞和凋亡，以及抑制Src活性及其下游效应物——抗凋亡Bcl-2家族。ZD6474治疗还可抑制STAT3的活性，其活性的重新激活会导致SFKs抑制剂的抗肿瘤作用受到抑制。单次口服ZD6474可产生剂量依赖性地抑制伊马替尼耐药K562细胞异种移植瘤。这些结果表明，有必要对ZD6474针对伊马替尼耐药慢性粒细胞白血病进行临床评估。
