DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex

Abstract

The dinuclear copper(II) complex [Cu 2 {bcmp(-H)}(μ-OH)](NO 3 ) 2 ·H 2 O (1, bcmp = 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol) has been synthesized and characterized by electrospray ionization mass spectrometry, potentiometric titration and cyclovoltammetry. The X-ray structure of the analogous perchlorate salt [Cu 2 {bcmp(-H)}(μ-OH)](ClO 4 ) 2 ·2.5H 2 O (2) was determined. Cytotoxicity studies showed very promising activity of 1 against various pancreatic tumor cell lines with IC 50 values comparable or even lower than those of cisplatin. The Cu complex displayed low toxicity against a human non-tumor cell line (HEK 293) demonstrating selectivity for cancer cells. 1 converts supercoiled pUC19 plasmid DNA into the nicked form at micromolar concentrations in the absence of added reductants. A detailed kinetic study on the hydrolysis of the DNA model bis(2,4-dinitrophenyl) phosphate (BDNPP) has been performed. 1 hydrolyses BDNPP with a second order rate constant of 0.047 M s −1 at pH 8 and 40°C. Finally, single cell electrophoresis (comet assay) and fluorescence microscopy analysis showed that 1 interacts with cellular DNA and induces apoptotic cell death of Capan-1 pancreatic cancer cells. Western blotting analysis indicated that the Cu complex activates the p53 dependent pathway of apoptosis.

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

“…Several studies demonstrated that cisplatin-induced cytotoxicity culminates in the activation of apoptosis in cancer cells [34][35][36] . The activation of apoptosis occurs through a mitochondrial membrane potential change and caspase-3 activation 37,38 .…”

Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors

“…Their complex interacts with DNA and activates the p53-dependent pathway of apoptosis. 17 Zhu and co-workers reported potent antitumoral activity against human cell lines (A549, Eca109 and SGC7901) for three mononuclear complexes containing the ligand H 2 TBHP (2-(3,5-di-tert-butyl-2-hydroxybenzylamino)-2-benzyl-acetic acid). The associated apoptosis is related to the effect of these copper(II) complexes on the expression of p53, Bax and Bcl-2.…”

Synthesis, characterization, DNA interaction, apoptosis and molecular docking of Cu(II) and Mn(II) complexes with endo‐norbornene‐cis‐5,6‐dicarboxylic acid

“…Under these conditions, the fluorescence intensity of the respective complexes, extracted HC‐DNA and ethidium bromide (EtBr) was very small and could be ignored. The interaction of the respective complexes with DNA in vitro was studied as described in the literature …”