Abstract 3806: Phosphaplatins are potent inducers of pigment epithelial- derived factor (PEDF)

Abstract

Abstract Pigment Epithelial Derived Factor (PEDF) is a secreted glycoprotein that exhibits several biological activities, most notably as a potent anti-angiogenic agent as well as a neurotrophic factor. As such, this molecule has potential application as therapeutics for cancer and a variety of neurological diseases. However, prior art methods directed towards enhancing and stabilizing PEDF expression in vivo have met with little success. Therefore, methods that could lead to the stable expression of PEDF in vivo are still needed. We have recently shown that PEDF protein is overexpressed in tumor cells treated with platinum based drugs; phosphaplatins that are platinum-(II) and platinum-(IV) complexes coordinated to a pyrophosphate moiety. The objective of this study is to extend our previous findings by measuring PEDF expression in both malignant cells and normal neuronal tissues after treating them with these compounds. We also investigated the impact of PEDF upregulation on important biological processes such as apoptosis, proliferation and invasion of tumor cells. Our data showed that there was a significant upregulation (over 4-fold) of PEDF in brain of mice treated with phosphoplatins when compared to the control animals. The compounds were found to stimulate PEDF expression in cultured neuronal cells when assessed in vitro (P<0.05 vs. untreated control groups). In tumor cells, phosphoplatins upregulated PEDF expression in a dose-dependent manner in various tumor cell lines. In one particular mouse breast tumor cell line (4T1), the data showed that phosphaplatin doses in the range of 25 to 100 μM stimulated the expression of PEDF at 12 and 24 hrs, which declined thereafter. Remarkably, a subsequent treatment of the tumor cells with phosphaplatins at 24 hrs prevented the decline of PEDF expression, suggesting a direct correlation between phosphaplatins and PEDF overexpression. The upregulation of PEDF in the tumor cells was paralleled by increased apoptosis and decreased cell proliferation and invasion. In summary, phosphaplatins mediated overexpression of PEDF in vivo suggests a potential neuroprotective effect of these compounds. While in tumors, phosphaplatins may exhibit antitumor activity via multiple effects, including anti-angiogenesis, enhanced apoptosis, and decreased proliferation and invasion, predominately through stimulating overexpression of PEDF. Citation Format: Louiza Belkacemi, Armando Rivera, Lu Yang, Rathindra N. Bose, Shaun X. Zhang. Phosphaplatins are potent inducers of pigment epithelial- derived factor (PEDF). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3806.