化学
促炎细胞因子
斑马鱼
转录因子
下调和上调
血管生成
癌症研究
NF-κB
磷酸化
血管内皮生长因子
αBκ
信号转导
细胞生物学
生物化学
炎症
基因
免疫学
血管内皮生长因子受体
生物
作者
Ayan Chakraborty,Shilpendu Ghosh,Manas Pratim Chakraborty,Shravanti Mukherjee,Shantanu Saha Roy,Rahul Das,Moulinath Acharya,Arindam Mukherjee
标识
DOI:10.1021/acs.jmedchem.4c00169
摘要
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.
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