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-κB) 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-κB 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-κB 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-γ 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-κB
and VEGFR2 by the complexes. The complexes are nontoxic to zebrafish
embryos up to 50 μM, but the ligands show strong in vivo antiangiogenic
activity at 3 μM during embryonic growth in Tg(fli1:GFP) zebrafish
but no visible effect on the adult phase.