ABT-263, a Bcl-2 inhibitor, enhances the susceptibility of lung adenocarcinoma cells treated with Src inhibitors to anoikis
ABT-263, a Bcl-2 inhibitor, enhances the susceptibility of lung adenocarcinoma cells treated with Src inhibitors to anoikis
复制标题
DOI：
10.3892/or.2010.1123
复制
发表时间：
2011-03-01
期刊：
影响因子：
4.2
通讯作者：
Miyagi, Yohei
中科院分区：
文献类型：
--
作者：
Sakuma, Yuji;Tsunezumi, Jun;Miyagi, Yohei
酪氨酸激酶Src在肺腺癌失巢凋亡抵抗的发生中起重要作用。几种表达磷酸化Src的悬浮肺腺癌细胞系在Src激酶抑制剂存在下发生凋亡或失巢凋亡。然而，肺腺癌细胞系对Src抑制剂的敏感性不同。我们假设，ABT-263，一种有效的Bcl-2抑制剂，应显着增强Src抑制剂处理的肺腺癌细胞的失巢凋亡的程度。在这项研究中，我们用ABT-263、Src抑制剂（博舒替尼或PP I）或两者的组合处理了四种悬浮肺腺癌细胞系。在LC-KJ和HCC 827细胞中，ABT-263和Src抑制剂的联合治疗有效地诱导了失巢凋亡，并且失巢凋亡的程度显著大于单独使用每种药物诱导的失巢凋亡;两种药物之间的协同作用是明显的。虽然我们没有观察到单独用ABT-263处理的LC-KJ和HCC 827细胞中失巢凋亡的显著增加，但用ABT-263（1 μ M）处理的H1650和H1975细胞在脱离后显著经历了凋亡，其水平远高于在附着后观察到的水平。然而，在H1650和H1975细胞中，联合治疗诱导的失巢凋亡水平仍高于单独药物诱导的失巢凋亡水平。这些发现为在肺腺癌患者中测试ABT-263和Src抑制剂的联合治疗提供了生物学依据。
The tyrosine kinase Src plays an important role in the development of anoikis resistance in lung adenocarcinomas. Several suspension lung adenocarcinoma cell lines, which express phosphorylated Src, undergo apoptosis, or anoikis, in the presence of Src kinase inhibitors. However, lung adenocarcinoma cell lines vary in their sensitivity to Src inhibitors. We hypothesized that the addition of ABT-263, a potent Bcl-2 inhibitor, should significantly enhance the degree of anoikis in lung adenocarcinoma cells treated with Src inhibitors. In this study, we treated four suspension lung adenocarcinoma cell lines with ABT-263, an Src inhibitor (bosutinib or PP I), or a combination of both. In LC-KJ and HCC827 cells, combined treatment with ABT-263 and an Src inhibitor effectively induced anoikis, and the extent of anoikis was significantly greater than that induced by each agent alone; the synergy between the two drugs was apparent. Although we did not observe a marked increase in anoikis in LC-KJ and HCC827 cells treated with ABT-263 alone, H1650 and H1975 cells treated with ABT-263 (1 mu M) upon detachment significantly underwent apoptosis, the levels of which were much greater than those observed upon attachment. However, the levels of anoikis induced by combination treatment were still greater than those by the individual agents in H1650 and H1975 cells. These findings provide a biological rationale to test combination therapy with ABT-263 and Src inhibitors in patients with lung adenocarcinoma.