期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 21, 页码 7613-7624出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm1009296
关键词
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资金
- National Basic Research Program (973 Program) [2007CB815800]
- International S&T Cooperation Program [2007DFA30840]
- State High-Tech Development Program (863 Program) [2006AA090504, 2007AA091401, 2008AA09Z401]
- China Postdoctoral Science Foundation [20080440790]
- Commission of Science and Technology of Guangdong Province and Guangzhou City
- Sun Yet-sen University Science Foundation
- National Natural Science Foundation of China
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 beta-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-Gl 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.
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