Ruthenium complexes with phenylterpyridine derivatives target cell membrane and trigger death receptors-mediated apoptosis in cancer cells.
Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs.
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Zhiqin
Z
Deng
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Pan
P
Gao
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Lianling
L
Yu
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Bin
B
Ma
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Yuanyuan
Y
You
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Leung
L
Chan
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Chaoming
C
Mei
Department of Chemistry, Jinan University, Guangzhou 510632, China. Electronic address: tchentf@jnu.edu.cn.
Tianfeng
T
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000493:pharmacokinetics / Q000494:pharmacology*; D004249:DNA Damage; D004705:Endocytosis; D006801:Humans; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D011725:Pyridines; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D011990:Receptors, Transferrin; D016159:Tumor Suppressor Protein p53; D012428:Ruthenium; D020169:Caspases; D002945:Cisplatin
Anticancer; Apoptosis; Cell membrane receptors; Ruthenium complex; Structure-activity relationship