Insights into the anti-angiogenic properties of phosphaplatins

Phosphaplatins are platinum-based antitumor compounds that, unlike other clinically utilized platinum drugs (i.e. cisplatin, carboplatin, and oxaliplatin), appear to target proteins rather than 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) and Pt(IV) phosphaplatins possess diverse antitumor properties. In addition to targeting apoptosis antigen (FAS) and proapoptotic gene products as described previously, phosphaplatins also target angiogenesis. We demonstrate that phosphaplatins 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 VEGFR-2 receptor 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 the phosphaplatin antitumor agents, which could potentially be used as chemotherapeutic agents against cisplatin-resistant cancers. The platinum agents phosphaplatin exhibit anti-cancer mechanisms that are different from those of the classical platinum drug cisplatin. The following work demonstrates that phosphaplatin can induce anti-angiogenesis in both in vitro and in vivo experiments. Phosphaplatin downregulates gene expression of growth factors/receptors and can bind to protein targets. [Display omitted] •Pt(II) and Pt(IV) complexes inhibit angiogenesis in human umbilical vein endothelial cells.•Phosphaplatins reduce the tumor size in tumor-xenografted mice.•A possible new class of anticancer agents against cisplatin-resistant tumors.