Nuclear permeable ruthenium(II) β-carboline complexes induce autophagy to antagonize mitochondrial-mediated apoptosis.
The role of autophagy in cancer development and response to cancer therapy has been a subject of debate. Here we demonstrate that a series of ruthenium(II) complexes containing a β-carboline alkaloid as ligand can simultaneously induce autophagy and apoptosis in tumor cells. These Ru(II) complexes are nuclear permeable and highly active against a panel of human cancer cell lines, with complex 3 displaying activities greater than those of cisplatin. The antiproliferative potentialities of 1-3 are in accordance with their relative lipophilicities, cell membrane penetration abilities, and in vitro DNA binding affinities. Complexes 1-3 trigger release of reactive oxygen species (ROS) and attenuation of ROS by scavengers reduced the sub-G1 population, suggesting ROS-dependent apoptosis. Inhibition of ROS generation also reduces autophagy, indicating that ROS triggers autophagy. Further studies show that suppression of autophagy using pharmacological inhibitors (3-methyladenine and chloroquine) enhances apoptotic cell death.
Tan
Caiping
C
State Key Laboratory of Biocontrol, Department of Biochemistry, College of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, PR China.
Lai
Sensen
S
Wu
Shouhai
S
Hu
Sheng
S
Zhou
Lingjun
L
Chen
Yu
Y
Wang
Minxu
M
Zhu
Yiping
Y
Lian
Wu
W
Peng
Wenlie
W
Ji
Liangnian
L
Xu
Anlong
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000378:metabolism*; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012428:Ruthenium; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002243:Carbolines; D056831:Coordination Complexes; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D049452:Green Fluorescent Proteins; D012428:Ruthenium; D004247:DNA