Cis-[Pt(Cl)₂(pyridine)(5-SO₃H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme

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.