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

// Lanmei Chen 1, * , Guodong Li 1, * , Fa Peng 1 , Xinming Jie 2 , Guangzhi Dongye 2 , Kangrong Cai 2 , Ruibing Feng 3 , Baojun Li 1 , Qingwang Zeng 1 , Kaiyi Lun 1 , Jincan Chen 2, 4 , Bilian Xu 1, 4 1 School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China 2 Analysis Centre of Guangdong Medical University, Zhanjiang, 524023, China 3 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, 999078, China 4 Guangdong 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: jincanchen@126.com Bilian Xu, email: gdmcxu@126.com Keywords: ruthenium imidazole complex, cytotoxicity, apoptosis, autophagy, reactive oxygen species Received: January 22, 2016      Accepted: October 26, 2016      Published: November 02, 2016 ABSTRACT 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.