A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells.

Fiche publication

Date publication

octobre 2018

Journal

Journal of inorganic biochemistry

Auteurs

Membres identifiés du Cancéropôle Est :
Dr MULLER Christian

Tous les auteurs :
Bjelogrlić S, Todorović TR, Cvijetić I, Rodić MV, Vujčić M, Marković S, Araškov J, Janović B, Emhemmed F, Muller CD, Filipović NR

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30352315

Résumé

A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production with dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 μM induces disintegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.