title: Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme.
abstract: Since it has been widely demonstrated that platinum-based drugs, like cisplatin, carboplatin and oxaliplatin, bind preferentially to guanine in N7 position and that telomerase assemblage includes a RNA portion rich in guanine, we previously designed and synthesized a series of new complexes with a cytotoxic [Pt(II)Cl2] moiety, with the aim of selecting carrier ligands able to inhibit telomerase enzyme. Among these compounds, [cis-dichloropyridine-5-isoquinolinesulfonic acid Pt(II)], named Ptquin8, showed the most significant inhibition of telomerase in a cell-free biochemical assay. In this paper, we report the biological effects of Ptquin8 on in vitro tumor model (MCF-7). This complex is able to reduce telomerase activity from 12 to 46%, in a concentration range between 10(-9) and 10(-5) M after 24 h continuous treatment. Moreover, Ptquin8 shows significant cytotoxicity after 10 days of continuous treatment only at concentrations higher than 10(-5) M. The determination of residual telomere length confirmed the inhibition of telomerase action. This induced a progressive reduction of the cell proliferative capacity, and the appearance of an elevated number of apoptotic cells after 18 days. RT-PCR analysis of telomerase RNA components excluded any interaction of the compound at genomic level. The biochemical effects of Ptquin8 were also evaluated on non-neoplastic NIH3T3 cells, that are able to down-regulate telomerase activity as a consequence of the confluence contact inhibition. In this cell model, the reactivation of telomerase due to re-seeding at lower density was significantly inhibited by Ptquin8 in a dose-dependent manner. These results highlight a possible role of Ptquin8 as a selective anti-telomerase tool for cancer treatment.
authors.affiliation: Dipartimento di Scienze Mediche, Università del Piemonte Orientale A. Avogadro, via Solaroli, 17, I-28100 Novara, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Colangelo
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Ghiglia
authors.forename: Ilario
authors.initials: I
authors.lastname: Viano
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavigiolio
authors.forename: Domenico
authors.initials: D
authors.lastname: Osella
mesh_terms: D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological; D015394:Molecular Structure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D012333:RNA, Messenger; D019098:Telomerase; C039109:isoquinoline