Inhibition of NF-κB-Mediated Proinflammatory Transcription by Ru(II) Complexes of Anti-Angiogenic Ligands in Triple-Negative Breast Cancer

Nuclear factor kappa beta (NF-kappa B) plays a pivotal role in breast cancer, particularly triple-negative breast cancer, by promoting inflammation, proliferation, epithelial-mesenchymal transition, metastasis, and drug resistance. Upregulation of NF-kappa B boosts vascular endothelial growth factor (VEGF) expression, assisting angiogenesis. The Ru(II) complexes of methyl- and dimethylpyrazolyl-benzimidazole N,N donors inhibit phosphorylation of ser536 in p65 and translocation of the NF-kappa B heterodimer (p50/p65) to the nucleus, disabling transcription to upregulate inflammatory signaling. The methyl- and dimethylpyrazolyl-benzimidazole inhibit VEGFR2 phosphorylation at Y1175, disrupting downstream signaling through PLC-gamma and ERK1/2, ultimately suppressing Ca(II)-signaling. Partial release of the antiangiogenic ligand in a reactive oxygen species-rich environment is possible as per our observation to inhibit both NF-kappa B and VEGFR2 by the complexes. The complexes are nontoxic to zebrafish embryos up to 50 mu M, but the ligands show strong in vivo antiangiogenic activity at 3 mu M during embryonic growth in Tg(fli1:GFP) zebrafish but no visible effect on the adult phase.