title: Insights into the anti-angiogenic properties of phosphaplatins.
abstract: 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 and31P 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.
authors: Departments of Chemistry, University of Houston, Houston, TX 77004, United States.
authors: Lu
authors: L
authors: Yang
authors: Departments of Biology and Biochemistry, University of Houston, Houston, TX 77004, United States.
authors: Shadi
authors: S
authors: Moghaddas
authors: Departments of Biology and Biochemistry, University of Houston, Houston, TX 77004, United States.
authors: Homa
authors: H
authors: Dezvareh
authors: Departments of Biology and Biochemistry, University of Houston, Houston, TX 77004, United States.
authors: Louiza
authors: L
authors: Belkacemi
authors: Departments of Biology and Biochemistry, University of Houston, Houston, TX 77004, United States.
authors: Steven J
authors: SJ
authors: Bark
authors: Departments of Chemistry, University of Houston, Houston, TX 77004, United States; Departments of Biology and Biochemistry, University of Houston, Houston, TX 77004, United States.
authors: Rathindra N
authors: RN
authors: Bose
authors: Departments of Chemistry, University of Houston, Houston, TX 77004, United States. Electronic address: loido@uh.edu.
authors: Loi H
authors: LH
authors: Do
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019014:fas Receptor; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2