Thati, Bhumika and Noble, Andy and Creaven, Bernadette S. and Walsh, Maureen and Kavanagh, Kevin and Egan, Denise A. (2007) Apoptotic cell death: A possible key event in mediating the in vitro anti-proliferative effect of a novel copper(II) complex, [Cu(4-Mecdoa) (phen)2] (phen=phenanthroline, 4-Mecdoa=4-methylcoumarin-6, 7-dioxactetate), in human malignant cancer cells. European Journal of Pharmacology, 569 (1-2). pp. 16-28. ISSN 0014-2999

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Abstract

The central objective of the current study was to investigate the potential in vitro anti-proliferative effect of the parent ligand, 4-methylcoumarin-6,7-dioxyacyeic acid (4-MecdoaH(2)), and its copper (II) complex, bis(phenanthroline4-methylcoumarin-6,7-dioxacetatocopper(II) ([Cu(4-Mecdoa)(phen)(2)]) using four human model cell lines. In addition, selected mechanistic studies were carried out using the most sensitive of the four cell lines. Results obtained show that the complex could alter proliferation of both human neoplastic renal (A-498) and hepatic (HepG2) cells. Furthermore, non-neoplastic hepatic (CHANG) cells appeared to be less sensitive. However, this effect was not duplicated with non-neoplastic renal (HK-2) cells, a profile shared by cisplatin. The observed anti-proliferative effect appeared to be dose-and time-dependent, and could be attributed to the complex, rather than any of the free components i.e. the 1,10-phenanthroline or coumarin ligand, or the simple metal salt. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Based on IC(50) values, [Cu(4-Mecdoa)(phen)(2)] was shown to be almost 12 times more potent than cisplatin. Moreover, there was no evidence that P-glycoprotein-mediated multi-drug resistance was likely to decrease anti-proliferative activity. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein], showed that cell death could switch between apoptosis and necrosis, and this effect appeared to be concentration-dependent. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Cu(4-Mecdoa)(phen)(2)] has been shown to be a more potent anti-proliferative agent than either the ligand or cisplatin, and is capable of altering key biochemical events leading to the execution of apoptotic and/or necrotic cell death, suggesting that it is worthy of further investigation.

Item Type:	Article
Keywords:	Apoptosis; Caspase activity; PARP cleavage; Cell cycle progression; Copper–coumarin–phenanthroline complex;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	7573
Identification Number:	https://doi.org/10.1016/j.ejphar.2007.04.064
Depositing User:	Dr. Kevin Kavanagh
Date Deposited:	26 Oct 2016 13:48
Journal or Publication Title:	European Journal of Pharmacology
Publisher:	Elsevier
Refereed:	Yes
Funders:	Technological Sector Research Programme, Strand III
URI:	http://www.sciencedirect.com
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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