Nuclear Permeable Ruthenium(II) β-Carboline Complexes Induce Autophagy To Antagonize Mitochondrial-Mediated Apoptosis

• Published in: Journal of medicinal chemistry Vol. 53; no. 21; pp. 7613 - 7624
• Main Authors: Tan, Caiping, Lai, Sensen, Wu, Shouhai, Hu, Sheng, Zhou, Lingjun, Chen, Yu, Wang, Minxu, Zhu, Yiping, Lian, Wu, Peng, Wenlie, Ji, Liangnian, Xu, Anlong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.11.2010
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - pharmacology; Cell Line, Tumor; Cell Membrane Permeability; Cell Nucleus - metabolism; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; DNA - chemistry; Drug Screening Assays, Antitumor; Green Fluorescent Proteins - genetics; Humans; Microscopy, Confocal; Microscopy, Electron, Transmission; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria - physiology; Reactive Oxygen Species - metabolism; Ruthenium; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm1009296

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.