New findings on the antiproliferative activity of the silver(I) complex with 5-fluorouracil against human multi-resistant NCI/ADR-RES ovarian tumor cells

• Published in: Toxicology in vitro 2019-10, Vol.60, p.359-368
• Main Authors: Bormio Nunes, Julia H., de Paiva, Paula P., Ruiz, Ana Lúcia T.G., de Carvalho, João Ernesto, Corbi, Pedro P.
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Activation; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin; Colonies; Coordination compounds; Depolarization; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Female; Flow cytometry; Fluorouracil - pharmacology; G1 phase; Humans; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Metal complex; Metal complexes; Mitochondria; Ovarian Neoplasms - drug therapy; Ovarian tumor; Phosphatidylserine; Phosphatidylserines - metabolism; Reactive oxygen species; Silver; Silver - pharmacology; Silver(I); Tumor cells
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2019.06.018

Metal complexes with antitumor activities have been studied as an alternative to overcome tumor resistance to current pharmaceuticals. Recently, we described the synthesis of a silver(I) complex with 5-fluorouracil (Ag-5fu) with an effective activity in vitro against human multi-resistant ovarian tumor cells (NCI/ADR-RES) when compared to 5-fluorouracil (5fu) and cisplatin. Therefore, for a better understanding of the effect of Ag-5fu and its precursors 5fu and silver(I), the compounds were evaluated by colony formation capacity and flow cytometry assays to analyze cell cycle and cell death induction [phosphatidylserine residues (PS) exposition, multicaspases activation, production of reactive oxygen species (ROS) and mitochondrial membrane depolarization] on NCI/ADR-RES tumor cells. As observed for 5fu, Ag-5fu was able to promote G1 phase arrest and to totally inhibit colony formation. Besides, as observed to AgNO3, Ag-5fu promoted a potent PS externalization and multicaspases activation with loss of plasmatic membrane integrity. None of the compounds induced reactive oxygen species (ROS) generation. The Ag-5fu promoted mitochondrial membrane depolarization over time. The results suggest that Ag-5fu may induce regulated cell death in NCI/ADR-RES cells probably by intrinsic apoptosis. Silver(I) and 5fu play different roles on the effect of Ag-5fu in NCI/ADR-RES cells, and the activity of the Ag-5fu complex seems to be more than a simple combination of the activities of free 5fu and silver(I) ions. [Display omitted] •Flow cytometry assays of a silver complex with 5-fluorouracil (Ag-5fu) are reported.•The complex arrests multi-resistant ovarian tumor cells NCI/ADR-RES cycle in G1 phase.•The complex was able to totally inhibit colony formation of NCI/ADR-RES.•Phosphatidylserine residues externalization and caspases activation were observed.•The Ag-5fu complex caused mitochondrial membrane depolarization in NCI/ADR-RES cells.