Abstract
Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treatment led to increased DNA breaks. Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival. Pt-ctpy can act in synergy with radiation for efficient killing of cancer cells at concentrations at which it has no obvious toxicity per se, opening perspectives for future therapeutic applications.
Highlights
Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions
We found that submicromolar concentrations of Pt-ctpy (0.05 and 0.1 μ M) reduced the proliferation of glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC) cells in a concentration-dependent manner
Treated cells accumulated in the S-phase and GBM cells were blocked in the G2/M-phase
Summary
Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. In non-small cell lung cancer (NSCLC), concomitant platinum-based chemotherapy and radiotherapy is the standard treatment for locally advanced stage III disease[2]. Targeting telomeres and/or telomerase by small molecules is a promising strategy for cancer treatment[8] In this context, we have been interested in targeting of DNA secondary structures called G-quadruplexes, which are formed in G-rich regions such as telomeres[9]. We have been interested in targeting of DNA secondary structures called G-quadruplexes, which are formed in G-rich regions such as telomeres[9] The stabilization of these structures using small molecule ligands may induce a strong DNA damage response at telomeres[10]. Quadruplex-targeting molecules (quadruplex ligands or G4-ligands) cause telomere uncapping by displacement of protective proteins and affect telomerase function[10,11,12,13,14,15]
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