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

• A bis(triazacyclonane) dicopper complex is reported that cleaves DNA in Capan-1 cells.
• The complex shows very promising activity against various pancreatic tumor cell lines.
• The complex can activate apoptotic cell death pathways by a mechanism that is p53-dependent.

The dinuclear copper(II) complex [Cu2{bcmp(-H)}(μ-OH)](NO3)2·H2O (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 [Cu2{bcmp(-H)}(μ-OH)](ClO4)2·2.5H2O (2) was determined. Cytotoxicity studies showed very promising activity of 1 against various pancreatic tumor cell lines with IC50 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.

A new dinuclear bis(triazacyclonane) copper complex is reported that represents a “self-activating” metallonuclease with interesting cytotoxic activity against pancreatic cancer cell lines.Figure optionsDownload as PowerPoint slide