Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

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.

High-resolution three-dimensional NMR structure of the KRAS proto-oncogene promoter reveals key features of a G-quadruplex involved in transcriptional regulation

“…G-quadruplexes are highly polymorphic, and sequences with G4-forming potential are suggested to be formed in different key genomic regions, mainly in telomeres and gene promoters. Recently, high-resolution models of several different folding topologies have been reported, and some were highlighted in the aim to develop interesting pharmacological compounds that could be exploited as new anticancer drugs (47,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64). The G4 structure presented here is in agreement with the topology calculated for 21R (50) using DMS footprinting and may serve as a template to target and design new drugs that may diminish or inhibit KRAS expression.…”

Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting

“…Despite their remarkable cellular properties, it is not clear currently whether G4-ligands can be used alone as efficient anticancer drugs (see reviews (14,30,31) ) with a few exceptions (see (32,33) ). In counterpart combinations with other anticancer treatments are more promising and a number of G4 targeting compounds have shown synergistic activity with classical cytotoxic drugs (31,34) and radiotherapy treatments, which has been validated in preclinical studies for some cases (35)(36)(37) . Alternatively G4 ligands like PDS or PDC (Scheme 1) have been exploited to direct or redirect classical DNA alkylating agents (chlorambucil, or benzophenone) using conjugate scaffolds in which the active principle is linked to the G4 recognition moiety (38,39) .…”

The G‐quadruplex‐stabilizing ligand RHPS4 enhances sensitivity of U251MG glioblastoma cells to clinical carbon ion beams

“…In particular, using a first-generation G4-ligand TAC, it was shown its capability to enhance in vitro c-rays-induced killing in SF763 and SF767T human radioresistant telomerase-positive GBM cell lines [26]. Similar results were obtained using a second-generation G4-ligand named Pt-ctpy that strongly enhances the sensitivity of GBM and nonsmall cell lung cancer cells (NSCLC) to ionizing radiation both in vitro and in SF763-GBM-xenografted mice [27]. Concerning the combined effect of RHPS4 and X-rays in cultured U251MG cells, evidence have been published which link dysfunctional telomeres with increased cell killing, persistent DNA damage, and chromosome aberrations [21].…”