Platinum Complexes Targeting Energy Metabolism of Cancer Cells

【作者】 王晓勇；

【Author】 Wang,Xiaoyong;School of Life Sciences,Nanjing University;

【机构】 南京大学；

【摘要】 Platinum-based anticancer drugs usually bind to purine bases through covalent bonds to inhibit DNA replication and cause cell death.However,systemic toxicity and drug resistance frequently undermine the clinical application of these drugs.To overcome the side effects,developing complexes capable of interacting with other targets besides DNA is a promising direction for future drug discovery.We recently designed a series of novel platinum complexes,including platinum（Ⅱ） and platinum（Ⅳ） complexes,with cellular energy metabolism and/or key enzymes involved in the glycolysis as the main targets.^[1-5] On the whole,these complexes markedly changed the ultrastructure and membrane of mitochondria,and exerted strong inhibition to both mitochondrial and glycolytic bioenergetics.Moreover,they could inhibit the activity of thioredoxin reductase（TrxR） or pyruvate dehydrogenase kinases（PDKs） related to the emery metabolisms of cancer cells.As a result,these complexes exhibited higher cytotoxicity against cisplatin-insensitive cancer cells and less toxicity to normal cells than cisplatin.The results indicate that in addition to binding DNA,targeting bioenergetic pathways could also produce powerful impact on the antitumor activity of platinum complexes.Platinum complexes with energy metabolism as alternative cellular target could achieve anticancer efficacy unattainable for traditional platinum drugs.更多还原

【Abstract】 Platinum-based anticancer drugs usually bind to purine bases through covalent bonds to inhibit DNA replication and cause cell death.However,systemic toxicity and drug resistance frequently undermine the clinical application of these drugs.To overcome the side effects,developing complexes capable of interacting with other targets besides DNA is a promising direction for future drug discovery.We recently designed a series of novel platinum complexes,including platinum（Ⅱ） and platinum（Ⅳ） complexes,with cellular energy metabolism and/or key enzymes involved in the glycolysis as the main targets.^[1-5] On the whole,these complexes markedly changed the ultrastructure and membrane of mitochondria,and exerted strong inhibition to both mitochondrial and glycolytic bioenergetics.Moreover,they could inhibit the activity of thioredoxin reductase（TrxR） or pyruvate dehydrogenase kinases（PDKs） related to the emery metabolisms of cancer cells.As a result,these complexes exhibited higher cytotoxicity against cisplatin-insensitive cancer cells and less toxicity to normal cells than cisplatin.The results indicate that in addition to binding DNA,targeting bioenergetic pathways could also produce powerful impact on the antitumor activity of platinum complexes.Platinum complexes with energy metabolism as alternative cellular target could achieve anticancer efficacy unattainable for traditional platinum drugs.更多还原