title: Photo-induced DNA cleavage and cytotoxicity of a ruthenium(II) arene anticancer complex.
abstract: We report DNA cleavage by ruthenium(II) arene anticancer complex [(η(6)-p-terp)Ru(II)(en)Cl](+) (p-terp=para-terphenyl, en=1,2-diaminoethane, complex 1) after its photoactivation by UVA and visible light, and the toxic effects of photoactivated 1 in cancer cells. It was shown in our previous work (T. Bugarcic et al., J. Med. Chem. 51 (2008) 5310-5319) that this complex exhibits promising toxic effects in several human tumor cell lines and concomitantly its DNA binding mode involves combined intercalative and monofunctional (coordination) binding modes. We demonstrate in the present work that when photoactivated by UVA or visible light, 1 efficiently photocleaves DNA, also in hypoxic media. Studies of the mechanism underlying DNA cleavage by photoactivated 1 reveal that the photocleavage reaction does not involve generation of reactive oxygen species (ROS), although contribution of singlet oxygen ((1)O2) to the DNA photocleavage process cannot be entirely excluded. Notably, the mechanism of DNA photocleavage by 1 appears to involve a direct modification of mainly those guanine residues to which 1 is coordinatively bound. As some tumors are oxygen-deficient and cytotoxic effects of photoactivated ruthenium compounds containing {Ru(η(6)-arene)}(2+) do not require the presence of oxygen, this class of ruthenium complexes may be considered potential candidate agents for improved photodynamic anticancer chemotherapy.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ 61265 Brno, Czech Republic. Electronic address: brabec@ibp.cz.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: Department of Biophysics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic; Department of Biophysics, Centre of the Region Hana for Biotechnological and Agricultural Research, Palacky University, Slechtitelu 27, 783 41 Olomouc, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Pracharova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ 61265 Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Stepankova
authors.affiliation: Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
authors.affiliation: Department of Biophysics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001483:Base Sequence; D002413:Cations, Divalent; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D053837:DNA Cleavage / Q000187:drug effects* / Q000528:radiation effects; D005029:Ethylenediamines / Q000737:chemistry*; D006801:Humans; D008027:Light; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010778:Photochemotherapy; D010957:Plasmids / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry*; D026082:Singlet Oxygen / Q000737:chemistry; D013730:Terphenyl Compounds / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D002413:Cations, Divalent; D056831:Coordination Complexes; D005029:Ethylenediamines; D009942:Organometallic Compounds; D013730:Terphenyl Compounds; D026082:Singlet Oxygen; C031234:ethylenediamine; D012428:Ruthenium; D004247:DNA
keywords: Antitumor activity; Comet assay; DNA cleavage; Photodynamic chemotherapy; Phototoxicity; Ruthenium anticancer complex