title: Potentiating effect of UVA irradiation on anticancer activity of Carboplatin derivatives involving 7-azaindoles.
abstract: The moderate-to-high in vitro cytotoxicity against ovarian A2780 (IC50 = 4.7-14.4 μM), prostate LNCaP (IC50 = 18.7-30.8 μM) and prostate PC-3 (IC50 = 17.6-42.3 μM) human cancer cell lines of the platinum(II) cyclobutane-1,1'-dicarboxylato complexes [Pt(cbdc)(naza)2] (1-6; cbdc = cyclobutane-1,1'-dicarboxylate(2-); naza = halogeno-substituted 7-azaindoles), derived from the anticancer metallodrug carboplatin, are reported. The complexes containing the chloro- and bromo-substituted 7-azaindoles (1, 2, and 4-6) showed a significantly higher (p < 0.05) cytotoxicity against A2780 cell line as compared to cisplatin used as a reference drug. Addition of the non-toxic concentration (5.0 μM) of L-buthionine sulfoximine (L-BSO, an effective inhibitor of γ-glutamylcysteine synthase) markedly increases the in vitro cytotoxicity of the selected complex 3 against A2780 cancer cell line by a factor of about 4.4. The cytotoxicity against A2780 and LNCaP cells, as well as the DNA platination, were effectively enhanced by UVA light irradiation (λmax = 365 nm) of the complexes, with the highest phototoxicity determined for compound 3, resulting in a 4-fold decline in the A2780 cells viability from 25.1% to 6.1%. The 1H NMR and ESI-MS experiments suggested that the complexes did not interact with glutathione as well as their ability to interact with guanosine monophosphate. The studies also confirmed UVA light induced the formation of the cis [Pt(H2O)2(cbdc`)(naza)] intermediate, where cbdc` represents monodentate-coordinated cbdc ligand, which is thought to be responsible for the enhanced cytotoxicity. This is further supported by the results of transcription mapping experiments showing that the studied complexes preferentially form the bifunctional adducts with DNA under UVA irradiation, in contrast to the formation of the less effective monofunctional adducts in dark.
authors: Regional Centre of Advanced Technologies and Materials & Department of Inorganic Chemistry, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors: Pavel
authors: P
authors: Štarha
authors: Regional Centre of Advanced Technologies and Materials & Department of Inorganic Chemistry, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors: Zdeněk
authors: Z
authors: Trávníček
authors: Regional Centre of Advanced Technologies and Materials & Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors: Zdeněk
authors: Z
authors: Dvořák
authors: Centre of the Region Haná for Biotechnological and Agricultural Research & Department of Biophysics, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors: Tereza
authors: T
authors: Radošová-Muchová
authors: Department of Biophysics, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors: Jitka
authors: J
authors: Prachařová
authors: Regional Centre of Advanced Technologies and Materials & Department of Inorganic Chemistry, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors: Ján
authors: J
authors: Vančo
authors: Department of Biophysics, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors: Jana
authors: J
authors: Kašpárková
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016190:Carboplatin / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D018736:DNA Adducts / Q000737:chemistry / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009690:Nucleic Acid Conformation; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D014466:Ultraviolet Rays
chemical_list: C023422:7-azaindole dimer; D000970:Antineoplastic Agents; D018736:DNA Adducts; D007211:Indoles; D019328:Buthionine Sulfoximine; D016190:Carboplatin