The induction of autophagy against mitochondria-mediated apoptosis in lung cancer cells by a ruthenium (II) imidazole complex.
The induction of autophagy against mitochondria-mediated apoptosis in lung cancer cells by a ruthenium (II) imidazole complex.
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DOI：
10.18632/oncotarget.13032
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发表时间：
2016-12-06
期刊：
影响因子：
--
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Chen L;Li G;Peng F;Jie X;Dongye G;Cai K;Feng R;Li B;Zeng Q;Lun K;Chen J;Xu B
在本研究中，它被发现，钌（II）咪唑配合物[Ru（Im）4（dppz）]2+（Ru 1）可以诱导A549和NCI-H460细胞的生长抑制和凋亡。除了诱导细胞凋亡外，首次报道Ru 1在A549和NCI-H460细胞中诱导自噬反应，如自噬体、酸性囊泡细胞器（AVO）的形成和LC 3-II的上调所证明的。此外，清除活性氧（ROS）的抗氧化剂NAC或Tiron抑制细胞色素c的释放，caspase-3的活性，并最终拯救癌细胞从Ru 1介导的凋亡，这表明Ru 1诱导凋亡是部分caspase 3依赖于触发ROS介导的线粒体功能障碍在A549和NCI-H460细胞。进一步的研究表明，细胞外信号调节激酶（ERK）信号通路参与Ru 1诱导的A549和NCI-H460细胞自噬。此外，使用药理学抑制剂3-甲基腺嘌呤（3-MA）和氯喹（CQ）阻断自噬增强Ru 1诱导的凋亡，表明自噬在Ru 1处理的A549和NCI-H460细胞中的细胞保护作用。最后，体内荷A549异种移植物的小鼠，Ru 1以10或20 mg/kg剂量给药显著抑制肿瘤生长。
In the present study, it was found that the ruthenium (II) imidazole complex [Ru(Im)4(dppz)]2+ (Ru1) could induce significant growth inhibition and apoptosis in A549 and NCI-H460 cells. Apart from the induction of apoptosis, it was reported for the first time that Ru1 induced an autophagic response in A549 and NCI-H460 cells as evidenced by the formation of autophagosomes, acidic vesicular organelles (AVOs), and the up-regulation of LC3-II. Furthermore, scavenging of reactive oxygen species (ROS) by antioxidant NAC or Tiron inhibited the release of cytochrome c, caspase-3 activity, and eventually rescued cancer cells from Ru1-mediated apoptosis, suggesting that Ru1 inducing apoptosis was partially caspase 3-dependent by triggering ROS-mediated mitochondrial dysfunction in A549 and NCI-H460 cells. Further study indicated that the extracellular signal-regulated kinase (ERK) signaling pathway was involved in Ru1-induced autophagy in A549 and NCI-H460 cells. Moreover, blocking autophagy using pharmacological inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhanced Ru1-induced apoptosis, indicating the cytoprotective role of autophagy in Ru1-treated A549 and NCI-H460 cells. Finally, the in vivo mice bearing A549 xenografts, Ru1 dosed at 10 or 20 mg/kg significantly inhibited tumor growth.