title: Antiangiogenic ruthenium(ii) benzimidazole complexes, structure-based activation of distinct signaling pathways.
abstract: Antiangiogenic therapy is considered to be a promising strategy for the treatment of cancers. VEGF and its receptors are important angiogenic factors involved in tumor growth. In the present study, the new ruthenium(ii) complexes containing 2,6-bis(benzimidazolyl)pyridine have been identified as potent antiangiogenic agents in vitro and in vivo, through activation of distinct antiangiogenic signaling pathways. Specifically, [Ru(bbp)(p-mpip)Cl]ClO4 (complex , bbp = 2,6-bis(benzimidazolyl)pyridine; p-mpip = 2-(4-methylphenyl)imidazo[4,5-f]-1,10-phenanthroline) exhibited the highest antiangiogenic activity, as evidenced by significant suppression of neovessel formation in chick chorioallantoic membranes and blockage of the angiogenesis in a matrigel plugs assay, which are significantly higher than those of the most accepted anti-metastasis ruthenium-based drug NAMI-A. Generally, these kinds of complexes induced the G0/G1cell cycle by inhibiting the formation of a Cyclin D1/CDK4 complex and CDK2 activation, through up regulation of the expression levels of p15(INK4B), p21(Cip1) and p27(Kip1). Moreover, the complexes also triggered intracellular DNA damage, and thus activated the phosphorylation of ATM, ATR, CHK1, Histone and p53. The suppression of Akt and ERK1/2 pathways reinforced the cell cycle perturbation effects of the complexes. Interestingly, complex displayed strong inhibition on the activation of VEGF and VEGFR-2 phosphorylation, which blocked the transmission of the mitogenic signal through Akt and ERK1/2 pathways, and thus enhanced cell cycle arrest. In contrast, we found that the most accepted anti-metastasis ruthenium based drug NAMI-A exerted lower antiangiogenic activity via activation of the DNA damage-mediated pathway, but showed no effects on VEGF and VEGFR-2 phosphorylation. Taken together, this study clearly demonstrates the distinct antiangiogenic mechanisms of metal complexes, and these kinds of complexes can be further developed as anti-vascularized drugs and as alternative agents of NAMI-A for the treatment of cancers.
authors: Department of Chemistry, Jinan University, Guangzhou 510632, China. tchentf@jnu.edu.cn.
authors: Haoqiang
authors: H
authors: Lai
authors: Zhennan
authors: Z
authors: Zhao
authors: Linlin
authors: L
authors: Li
authors: Wenjie
authors: W
authors: Zheng
authors: Tianfeng
authors: T
authors: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004249:DNA Damage; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012428:Ruthenium / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D056831:Coordination Complexes; D042461:Vascular Endothelial Growth Factor A; D012428:Ruthenium; C031000:benzimidazole; D040301:Vascular Endothelial Growth Factor Receptor-2