title: Anticancer potential of a photoactivated transplatin derivative containing the methylazaindole ligand mediated by ROS generation and DNA cleavage.
abstract: 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.
authors.affiliation: Department of Biophysics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 11, 783 41 Olomouc, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Pracharova
authors.affiliation: Department of Biophysics, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Radosova Muchova
authors.affiliation: Institute of Experimental Botany, Centre of the Region Haná for Biotechnological and Agricultural Research, Šlechtitelů 31, 78371 Olomouc, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Dvorak Tomastikova
authors.affiliation: Department of Chemistry, University of Bari "Aldo Moro", 70125 Bari, Italy.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Intini
authors.affiliation: Department of Chemistry, University of Bari "Aldo Moro", 70125 Bari, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Pacifico
authors.affiliation: Department of Chemistry, University of Bari "Aldo Moro", 70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.affiliation: Department of Biophysics, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic and Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, CZ-61265 Brno, Czech Republic. brabec@ibp.cz.
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, CZ-61265 Brno, Czech Republic. brabec@ibp.cz.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D053837:DNA Cleavage; D053938:DNA Fragmentation; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D008024:Ligands; D017382:Reactive Oxygen Species / Q000378:metabolism; D026082:Singlet Oxygen / Q000737:chemistry; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; D017382:Reactive Oxygen Species; C034697:transplatin; D026082:Singlet Oxygen; D004247:DNA; D002945:Cisplatin