Enhancement of Antiangiogenic Efficacy of Iron(II) Complex by Selenium Substitution

Antiangiogenesis therapy is a proven strategy for the treatment of cancers. Herein, we demonstrate that iron(II) complexes containing 1,10‐phenanthroline(phen) derivatives were capable of suppressing angiogenesis in vitro in a dose‐dependent manner. Interestingly, the introduction of selenium into an iron(II) complex ((Fe(phenSe)3(ClO4)2 (phenSe=2‐selenoimidazole[4,5‐f]1,10‐phenanthroline)) could enhance its antiangiogenic efficacy. Mechanistic studies demonstrated that the complex potently induced endothelial cell apoptosis as evidenced by activation of caspases and PARP cleavage. The iron(II) complex activated p53‐mediated mitochondrial dysfunction as can be seen by the upregulation in the expression of p53 and proapoptotic Bcl‐2 family proteins, and downregulation in the expression of Bcl‐2 family proteins. Additionally, the complex inhibited VEGF expression and gave rise to dephosphorylated AKT, which suppressed the transmission of the mitogenic signaling pathway. Taken together, this study could provide a strategy for the rational design of high‐efficacy antivascular agents.