Anticancer potential of a photoactivated transplatin derivative containing the methylazaindole ligand mediated by ROS generation and DNA cleavage

0463802 - ÚEB 2017 RIV GB eng J - Journal Article
Prachařová, J. - Muchová, T. - Tomaštíková, Eva - Intini, F. P. - Pacifico, C. - Natile, G. - Kašpárková, Jana - Brabec, Viktor
Anticancer potential of a photoactivated transplatin derivative containing the methylazaindole ligand mediated by ROS generation and DNA cleavage.
Dalton Transactions. Roč. 45, č. 33 (2016), s. 13179-13186. ISSN 1477-9226. E-ISSN 1477-9234
R&D Projects: GA ČR(CZ) GA14-21053S; GA MŠMT(CZ) LO1204
Institutional support: RVO:68081707 ; RVO:61389030
Keywords : PLATINUM-DIIMINE COMPLEX * SINGLET OXYGEN * SUPERCOILED DNA
Subject RIV: CE - Biochemistry
Impact factor: 4.029, year: 2016

The limitations associated with the clinical utility of conventional platinum anticancer drugs have stimulated research leading to the design of new metallodrugs with improved pharmacological properties, particularly with increased selectivity for cancer cells. Very recent research has demonstrated that photoactivation or photopotentiation of platinum drugs can be one of the promising approaches to tackle this challenge. This is so because the application of irradiation can be targeted exclusively to the tumor tissue so that the resulting effects could be much more selective and targeted to the tumor. We show in this work that the presence of 1-methyl-7-azaindole in trans-[PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compound 1) markedly potentiated the DNA binding ability of 1 when irradiated by UVA light in a cell-free medium. Concomitantly, the formation of cytotoxic bifunctional cross-links was markedly enhanced. In addition, 1, when irradiated with UVA, was able to effectively cleave the DNA backbone also in living cells. The incorporation of 1-methyl-7-azaindole moiety had also a profound effect on the photophysical properties of 1, which can generate singlet oxygen responsible for the DNA cleavage reaction. Finally, we found that 1, upon irradiation with UVA light, exhibited a pronounced dose-dependent decrease in viability of A2780 cells whereas it was markedly less cytotoxic if the cells were treated in the absence of light. Hence, it is possible to conclude that 1 is amenable to photodynamic therapy.
Permanent Link: http://hdl.handle.net/11104/0262893