The induction of autophagy against mitochondria-mediated apoptosis in lung cancer cells by a ruthenium (II) imidazole complex.
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.
School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China.
Lanmei
L
Chen
School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China.
Guodong
G
Li
School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China.
Fa
F
Peng
Analysis Centre of Guangdong Medical University, Zhanjiang, 524023, China.
Xinming
X
Jie
Analysis Centre of Guangdong Medical University, Zhanjiang, 524023, China.
Guangzhi
G
Dongye
Analysis Centre of Guangdong Medical University, Zhanjiang, 524023, China.
Kangrong
K
Cai
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, 999078, China.
Ruibing
R
Feng
School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China.
Baojun
B
Li
School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China.
Qingwang
Q
Zeng
School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China.
Kaiyi
K
Lun
Analysis Centre of Guangdong Medical University, Zhanjiang, 524023, China.|Guangdong Key Laboratory for Research and Development of Nature Drugs, Guangdong Medical University, Zhanjiang, 524023, China.
Jincan
J
Chen
School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, China.|Guangdong Key Laboratory for Research and Development of Nature Drugs, Guangdong Medical University, Zhanjiang, 524023, China.
Bilian
B
Xu
D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012428:Ruthenium / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007093:Imidazoles; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D012428:Ruthenium; D045304:Cytochromes c; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; D053148:Caspase 3
apoptosis; autophagy; cytotoxicity; reactive oxygen species; ruthenium imidazole complex