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

Abstract

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.

Exploring novel Cd(ii) complexes with 5-methyl-4-imidazolecarboxaldehyde: synthesis, structure, computational insights, and affinity to DNA through switchSense methodology

“…It has been shown that some of them directly target the DNA chain and inhibit of incorporation of 3H-thymidine into DNA. 14 Furthermore, they can target DNA non-covalently by groove binding, 15 intercalation, [16][17][18] or combinations of these two modes. 19 In addition to DNA, they can also be directed at other protein targets.…”

Three metal complexes with a pyridyl Schiff base: cytotoxicity, migration and mechanism of apoptosis

“…[5][6][7] Other transition metal complexes have also been synthesized and investigated with significant biological activity. [8][9][10] The biological activity of cadmium complexes has not been further investigated as it is well known that Cd has great toxicity to the human body and metabolizes slowly in the human body. However, it has been reported that the toxicity of Cd is comparable to the toxicity of noble metals, and metal toxicity is not a constant property and depends on many factors like the presence of appropriate ligands.…”

A detailed experimental and computational study of Cd complexes with pyridyl‐based thiazolyl hydrazones

“…They show potent anticancer activity and can kill cancer cells via programmed cell death apoptosis. [ 4 ]…”