Insights into the Properties of Platinum and Iridium Complexes in Cancer Chemotherapy



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Phosphaplatins are platinum (Pt)-based antitumor compounds that, unlike other clinically utilized Pt drugs (i.e, cisplatin, carboplatin, and oxaliplatin), appear to target proteins rather than deoxyribonucleic acid (DNA). Because of their unique mode of action, phosphaplatins are promising drug candidates for cisplatin-resistant cancers. In this study, we discovered that Pt(II) (RRD2) and Pt(IV) (RRD4) phosphaplatins possess diverse antitumor properties. In addition to targeting FAS and proapoptotic gene products, RRD2 and RRD4 also target angiogenesis. We demonstrate that RRD2 and RRD4 inhibit human umbilical vein endothelial cell (HUVEC) migration and tube formation in vitro and suppress tumor angiogenesis and growth in immunodeficient mice that were inoculated with A2780 ovarian cancer cells in vivo. To provide insight into this novel antitumor mechanism, phosphaplatin-treated HUVECs were found to exhibit lower gene expression levels of vascular endothelial growth factors (VEGFs) and the VEGF receptor-2 (VEGFR-2) compared to untreated cells. Kinase inhibition studies suggest that phosphaplatins are inhibitors of VEGFR-2. In ligand exchange experiments using both Pt atomic absorption and 31P NMR spectroscopies, we show that phosphaplatins most likely bind to VEGFR-2 through metal-ligand coordination rather than electrostatic interactions. These studies enhance our understanding of the diverse and novel mechanisms of action of phosphaplatin, which could potentially be used in chemotherapeutic approaches against cisplatin-resistant cancers. The efficacy of Pt drugs is greatly limited by drug resistance and their undesirable side effects. On strategy to lower the regulated therapeutic dose of Pt drugs is to use chemo-sensitizers. In this study, we also demonstrated that pentamethylcyclopentadienyl (Cp*) iridium (Ir) complexes can work synergistically with cisplatin/carboplatin in cancer treatment. The combined use of Ir complexes and Pt drugs enhanced the selective killing of cancerous cells over non-cancerous cells. The ability of these Ir complexes to induce intracellular oxidative stress by catalytic hydride transfer from the coenzyme NADH to oxygen is proposed. Our findings suggest that the application of Ir metallo-chemosensitizers can be an effective way to increase the efficacy of anti-cancer drugs.



Phosphaplatins, Angiogenesis, VEGFR-2, Ir metallo-chemosensitizers