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

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• 作者：Caiping Tan ; Sensen Lai ; Shouhai Wu ; Sheng Hu ; Lingjun Zhou ; Yu Chen ; Minxu Wang ; Yiping Zhu ; Wu Lian ; Wenlie Peng ; Liangnian Ji ; Anlong Xu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 11, 2010
• 年：2010
• 卷：53
• 期：21
• 页码：7613-7624
• 全文大小：1334K
• 年卷期：v.53,no.21(November 11, 2010)
• ISSN：1520-4804

文摘

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.