PUBLICATION
Inhibition of NF-κB-Mediated Proinflammatory Transcription by Ru(II) Complexes of Anti-Angiogenic Ligands in Triple-Negative Breast Cancer
- Authors
- Chakraborty, A., Ghosh, S., Chakraborty, M.P., Mukherjee, S., Roy, S.S., Das, R., Acharya, M., Mukherjee, A.
- ID
- ZDB-PUB-240324-5
- Date
- 2024
- Source
- Journal of medicinal chemistry 67(7): 5902-5923 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Benzimidazoles/pharmacology
- Humans
- NF-kappa B*/metabolism
- Ligands
- Vascular Endothelial Growth Factor A
- Transcription Factor RelA/metabolism
- Triple Negative Breast Neoplasms*/drug therapy
- Zebrafish/metabolism
- PubMed
- 38520399 Full text @ J. Med. Chem.
Citation
Chakraborty, A., Ghosh, S., Chakraborty, M.P., Mukherjee, S., Roy, S.S., Das, R., Acharya, M., Mukherjee, A. (2024) Inhibition of NF-κB-Mediated Proinflammatory Transcription by Ru(II) Complexes of Anti-Angiogenic Ligands in Triple-Negative Breast Cancer. Journal of medicinal chemistry. 67(7):5902-5923.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping