Dicyanoargentate(I)-based complexes induced in vivo tumor inhibition by activating apoptosis-related pathways

Abstract

Colorectal adenocarcinoma, which often occurs as a result of a typical chromosomal instability and mismatch repair deficiencies resulting in resistance to apoptosis, is a significant burden on society. Previously, we demonstrated strong apoptosis triggers Ag(I) complexes in vitro, including [Ni (hydeten)(2)Ag(CN)(2)] [Ag (CN2].H2O (C1), [Ni (bishydeten)(2)] [Ag (CN)(2)](2).H2O (C2), and [Ni(N-bishydeten)Ag-3(CN)(5)] (C3), which specifically induce the apoptotic mechanism of cancer cells and selectively is non-cytotoxic within normal cells. Herein, we introduce in vivo the ability of Ag(I) complexes to activate apoptosis and interact with cell cycle and cell fate-related proteins. To assess antitumor efficacy, we evaluated tumor volume, survival rate, and protein status related to cell cycle, apoptosis, and oxidative stress (by immunohistochemistry, genetic expression, and ELISA assays). In addition, in this study, using molecular docking study, the interactions of metal complexes on many proteins were examined, and the findings related to their theoretical anticancer activities were obtained and compared. The in vivo evaluation of Ag(I) complexes (10 mg/kg) against HT29 xenograft tumor model in the CD1 nude and BALB/c mice revealed a remarkable decrease in the tumor volume and increase survival rate. The weight-loss situation and histopathological indicators of Ag(I) complexes-treated mice approved that the Ag(I) complexes have a considerable healing effect on solid tumors with negligible side-effect on the tissue. This promising information strongly expresses that Ag(I) complexes may fulfill the task of an antitumor agent and be a potential candidate for a chemotherapeutic approach against colorectal adenocarcinoma.