Research Papers:

The induction of autophagy against mitochondria-mediated apoptosis in lung cancer cells by a ruthenium (II) imidazole complex

Lanmei Chen, Guodong Li, Fa Peng, Xinming Jie, Guangzhi Dongye, Kangrong Cai, Ruibing Feng, Baojun Li, Qingwang Zeng, Kaiyi Lun, Jincan Chen and Bilian Xu _

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Oncotarget. 2016; 7:80716-80734. https://doi.org/10.18632/oncotarget.13032

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Lanmei Chen1,*, Guodong Li1,*, Fa Peng1, Xinming Jie2, Guangzhi Dongye2, Kangrong Cai2, Ruibing Feng3, Baojun Li1, Qingwang Zeng1, Kaiyi Lun1, Jincan Chen2,4, Bilian Xu1,4

1School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China

2Analysis Centre of Guangdong Medical University, Zhanjiang, 524023, China

3State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, 999078, China

4Guangdong Key Laboratory for Research and Development of Nature Drugs, Guangdong Medical University, Zhanjiang, 524023, China

*These authors contributed equally to this work

Correspondence to:

Jincan Chen, email: [email protected]

Bilian Xu, email: [email protected]

Keywords: ruthenium imidazole complex, cytotoxicity, apoptosis, autophagy, reactive oxygen species

Received: January 22, 2016     Accepted: October 26, 2016     Published: November 02, 2016


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.

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