Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands

观察到带有磷烷共配体的新型联吡啶-银 (I) 化合物具有前所未有的作用方式,即旁凋亡细胞死亡

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作者:Ricardo G Teixeira, Alessia Stefanelli, Adhan Pilon, Rebecca Warmers, Xavier Fontrodona, Isabel Romero, Paulo J Costa, Maria J Villa de Brito, Xenia Hudec, Christine Pirker, Sebastian Türck, Alexandra M M Antunes, Christian R Kowol, Ingo Ott, Anamaria Brozovic, Andy Sombke, Margret Eckhard, Ana Isab

Abstract

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.

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