title: Platinum(II) phenanthroimidazole G-quadruplex ligand induces selective telomere shortening in A549 cancer cells.
abstract: Telomere maintenance, achieved by the binding of protective shelterin capping proteins to telomeres and by either telomerase or a recombination-based alternative lengthening of telomere (ALT) mechanism, is critical for cell proliferation and survival. Extensive telomere shortening or loss of telomere integrity activates DNA damage checkpoints, leading to cell senescence or death. Although telomerase upregulation is an attractive target for anti-cancer therapy, the lag associated with telomere shortening and the potential activation of ALT pose a challenge. An alternative approach is to modify telomere interactions with binding proteins (telomere uncapping). G-quadruplex ligands stabilize structures generated from single-stranded G-rich 3'-telomere end (G-quadruplex) folding, which in principle, cannot be elongated by telomerase, thus leading to telomere shortening. Ligands can also mediate rapid anti-proliferative effects by telomere uncapping. We previously reported that the G-quadruplex ligand, phenylphenanthroimidazole ethylenediamine platinum(II) (PIP), inhibits telomerase activity in vitro[47]. In the current study, a long-term seeding assay showed that PIP significantly inhibited the seeding capacity of A549 lung cancer cells and to a lesser extent primary MRC5 fibroblast cells. Importantly, treatment with PIP caused a significant dose- and time-dependent decrease in average telomere length of A549 but not MRC5 cells. Moreover, cell cycle analysis revealed a significant increase in G1 arrest upon treatment of A549 cells, but not MRC5 cells. Both apoptosis and cellular senescence may contribute to the anti-proliferative effects of PIP. Our studies validate the development of novel and specific therapeutic ligands targeting telomeric G-quadruplex structures in cancer cells.
authors.affiliation: Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada H3T 1E2; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mancini
authors.affiliation: Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada H3T 1E2.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousseau
authors.affiliation: Department of Chemistry, McGill University, Montréal, Québec, Canada H3A 2K6.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Castor
authors.affiliation: Department of Chemistry, McGill University, Montréal, Québec, Canada H3A 2K6.
authors.forename: Hanadi F
authors.initials: HF
authors.lastname: Sleiman
authors.affiliation: Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada H3T 1E2; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada. Electronic address: chantal.autexier@mcgill.ca.
authors.forename: Chantal
authors.initials: C
authors.lastname: Autexier
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D006801:Humans; D017671:Platinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D016615:Telomere / Q000187:drug effects; D059506:Telomere Shortening / Q000187:drug effects*
chemical_list: D017671:Platinum Compounds
keywords: Cancer; G-quadruplex ligand; Senescence; Telomerase; Telomere shortening