title: Insight into the toxic effects of cis-dichloridoplatinum(II) complexes containing 7-azaindole halogeno derivatives in tumor cells.
abstract: The cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian tumor cells, with moderately better IC50 values than for cisplatin in the cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular accumulation, different effects at the level of cell cycle regulation, and reduced propensity for DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, which is typically required for an active platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and cisplatin in tumor cells. The results of this work reinforce the idea that direct analogues of conventional cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents.
authors.affiliation: Department of Biophysics, Faculty of Sciences, Palacky University, 17. listopadu 12, 77146 Olomouc, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Muchova
authors.forename: Jitka
authors.initials: J
authors.lastname: Pracharova
authors.forename: Pavel
authors.initials: P
authors.lastname: Starha
authors.forename: Radana
authors.initials: R
authors.lastname: Olivova
authors.forename: Oldrich
authors.initials: O
authors.lastname: Vrana
authors.forename: Barbora
authors.initials: B
authors.lastname: Benesova
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Travnicek
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000633:toxicity*
chemical_list: D009944:Organoplatinum Compounds; D005978:Glutathione