Ruthenium complexes with phenylterpyridine derivatives target cell membrane and trigger death receptors-mediated apoptosis in cancer cells
| Autor: | Yuanyuan You, Lianling Yu, Chaoming Mei, Bin Ma, Zhiqin Deng, Pan Gao, Tianfeng Chen, Leung Chan |
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| Rok vydání: | 2016 |
| Předmět: |
Pyridines
Biophysics Mice Nude Bioengineering Antineoplastic Agents Apoptosis Biology 010402 general chemistry Endocytosis 01 natural sciences Models Biological Ruthenium Biomaterials Cell membrane Cell surface receptor Coordination Complexes Cell Line Tumor Neoplasms Spheroids Cellular Receptors Transferrin medicine Animals Humans Tissue Distribution Phosphorylation Cell Proliferation 010405 organic chemistry Cell Membrane Receptors Death Domain 0104 chemical sciences Cell biology medicine.anatomical_structure Mechanics of Materials Cytoplasm Caspases Cancer cell Ceramics and Composites Signal transduction Cisplatin Tumor Suppressor Protein p53 Reactive Oxygen Species Intracellular DNA Damage |
| Zdroj: | Biomaterials. 129 |
| ISSN: | 1878-5905 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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