Poster Presenter

Induction of Apoptotic Cell Death in Human Malignant Cell Lines by bis[(7e)-7-(3-ethoxy-2-hydroxybenzylideneamino)-4-methylquinolin-2(1h)-one]copper(II)perchlorate
B.R. Duff, V. Tangella, B.S. Creaven, M. Walsh, M. Mccann, K. Kavanagh, M. Devereux, D. A. Egan
Ireland

Interest in coumarins as potential anti-cancer agents arose from initial reports, where favorable responses were achieved in patients with advanced malignancies1. Our research group has shown that selected coumarins act by altering biochemical signals associated with cellular differentiation and death2,3. Furthermore, several reports have highlighted the use of transition metal complexes of coumarin as both anti-microbial and anti-cancer agents4,5. Quinolones are classically used to treat bacterial diseases however, their anti-cancer potential has been recently highlighted by Foroumadi et. al.6 This led our research group to focus considerable attention on determining the in vitro anti-proliferative effects of novel metal-based quinolone Schiff bases, using human-derived cancer cell lines. From these studies, one agent namely; bis[(7E)-7-(3-ethoxy-2-hydroxybenzylideneamino)-4-methylquinolin-2(1H)-one]copper(II)Perchlorate (TV117-FM) was shown to be most active, with IC50 values in the low micromolar range. Selected mechanistic studies have shown that this agent has comparable cytotoxicity to cisplatin. Furthermore, analysis of genomic DNA from drug-treated cells suggest the induction of apoptotic cell death, due to the presence of a ladder pattern so characteristic of this form of cell death. This result is further underpinned by morphological and biochemical evidence including; activation of caspase-3 & 9 and a disruption of cell cycle events. In conclusion, this novel metal-based quinolone Schiff base, and related compounds would appear to offer significant potential as chemotherapeutic agents for the successful treatment and management of cancer in man.
This research was supported by the Irish Technological Sector Research Strand III (2002 & 2006)

1. Egan, D. et al., Drug Metab. Rev. 1990 (22), 503-529.

2. Finn, G. et al., E. J. Pharm. 2003 (81), 159-167.

3. Finn, G. et al., Cancer Lett., 2004 (205), 69-79.

4. Irena, K. et al., E. J. Med. Chem. 2001, 18 (2), 161-165.

5 . Thati, B. et al., Eur. J. Pharm. 2009, (602), 203-214.