title: Mixed-ligand ruthenium polypyridyl complexes as apoptosis inducers in cancer cells, the cellular translocation and the important role of ROS-mediated signaling.
abstract: Ruthenium (Ru) polypyridyl complexes have emerged as leading players among the potential metal-based candidates for cancer treatment. However, the roles of cellular translocation in their action mechanisms remain elusive. Herein we present the synthesis and characterization of a series of ruthenium (Ru) complexes containing phenanthroline derivatives with varying lipophilicities, and examine their mechanism of anticancer action. Results showed that increasing the lipophilicity of complexes can enhance the rates of cellular uptake. The in vitro anticancer efficacy of these complexes depended on the levels of ROS overproduction, rather than on cellular Ru uptake levels. The introduction of a phenolic group on the ligand effectively enhanced their intracellular ROS generation and anticancer activities. In particular, complex 4, with an ortho-phenolic group on the ligand, exhibited better selectivity between cancer and normal cells in comparison with cisplatin. Notably, complex 4 entered the cancer cells partially through transferrin receptor-mediated endocytosis, and then it translocated from lysosomes to the mitochondria, where it activated mitochondrial dysfunction by regulation of Bcl-2 family proteins, thus leading to intracellular ROS overproduction. Excess ROS amplified apoptotic signals by activating many downstream pathways such as p53 and MAPK pathways to promote cell apoptosis. Overall, this study provides a drug design strategy for discovery of Ru-based apoptosis inducers, and elucidates the intracellular translocation of these complexes.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. tchentf@jnu.edu.cn tzhwj@jnu.edu.cn.
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Zhao
authors.forename: Zuandi
authors.initials: Z
authors.lastname: Luo
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
authors.forename: Yanxian
authors.initials: Y
authors.lastname: Feng
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D015082:2,2'-Dipyridyl; D012428:Ruthenium