Targeting telomerase and telomeres to enhance ionizing radiation effects in in vitro and in vivo cancer models

Berardinelli, Francesco; Coluzzi, Elisa; Sgura, Antonella; Antoccia, Antonio

doi:10.1016/j.mrrev.2017.02.004

Cited by 36 publications

(31 citation statements)

References 203 publications

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“…Telomere dysfunction has been associated with an increased response to IR [38][39][40]. Consequently telomere-and telomerase-targeting drugs may represent a powerful tool to increase radiotherapy outcome in radioresistant cancer treatment [41]. In contrast to RHPS4 [27], NDIs did not increase U251MG sensitivity to X-rays as shown by SF and long-term proliferation experiments.…”

Section: Discussionmentioning

confidence: 92%

Naphthalene diimide‐derivatives G‐quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

et al. 2018

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In the present paper, the biological effects of three different naphthalene diimides (NDIs) G-quadruplex (G4) ligands (H-NDI-Tyr, H-NDI-NMe2, and tetra-NDI-NMe2) were comparatively evaluated to those exerted by RHPS4, a well-characterized telomeric G4-ligand, in an in vitro model of glioblastoma. Data indicated that NDIs were very effective in blocking cell proliferation at nanomolar concentrations, although displaying a lower specificity for telomere targeting compared to RHPS4. In addition, differently from RHPS4, NDIs failed to enhance the effect of ionizing radiation, thus suggesting that additional targets other than telomeres could be involved in the strong NDI-mediated anti-proliferative effects. In order to test telomeric off-target action of NDIs, a panel of genes involved in tumor progression, DNA repair, telomere maintenance, and cell-cycle regulation were evaluated at transcriptional and translational level. Specifically, the compounds were able to cause a marked reduction of TERT and BCL2 amounts as well as to favor the accumulation of proteins involved in cell cycle control. A detailed cytofluorimetric analysis of cell cycle progression by means of bromodeoxyuridine (BrdU) incorporation and staining of phospho-histone H3 indicated that NDIs greatly reduce the progression through S-phase and lead to G1 accumulation of BrdU-positive cells. Taken together, these data indicated that, besides effects on telomeres and oncogenes such as Tert and Bcl2, nanomolar concentrations of NDIs determined a sustained block of cell proliferation by slowing down cell cycle progression during S-phase. In conclusion, our data indicate that NDIs G4-ligands are powerful antiproliferative agents, which act through mechanisms that ultimately lead to altered cell-cycle control.

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Section: Discussionmentioning

confidence: 92%

Naphthalene diimide‐derivatives G‐quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

et al. 2018

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“…Since the original discovery of telomerase and the observation that it is expressed abundantly in malignant compared with normal cells, telomerase inhibition has been intensively investigated as an anticancer strategy, including in combination with external beam radiation or chemotherapy. It has been demonstrated that telomere shortening caused by downregulation of telomerase results in radiosensitization (18)(19)(20)(21)(22)(23)(37)(38)(39), and, conversely, that increased telomerase expression is linked to apoptosis resistance and enhanced DNA repair (7). Telomerase protects aneuploid cells against replication stress, and promotes genomic stability in cancer cells (40,41).…”

Section: Discussionmentioning

confidence: 99%

“…One such inhibitor (GRN163L, Imetelstat) is undergoing clinical trials in patients with a variety of cancer indications and positive outcomes have been reported in patients with essential thrombocytopenia and myelofibrosis (16,17). Interestingly, it has been demonstrated that hTR inhibition results in chemo-and radiosensitization (18)(19)(20)(21)(22), which is attributed to both telomere length-dependent and -independent mechanisms (23).…”

Section: Introductionmentioning

confidence: 99%

Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells

et al. 2019

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Telomerase is expressed in the majority (>85%) of tumors, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterization of radiolabeled oligonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic activity and delivering radiation intracellularly. Oligonucleotides complementary (Match) and noncomplementary (Scramble or Mismatch) to hTR were conjugated to diethylenetriaminepentaacetic dianhydride (DTPA), allowing radiolabeling with the Auger electron-emitting radionuclide indium-111 (111 In). Match oligonucleotides inhibited telomerase activity with high potency, which was not observed with Scramble or Mismatch oligonucleotides. DTPA-conjugation and 111 In-labeling did not change telomerase inhibition. In telomerase-positive cancer cells, unlabeled Match oligonucleotides had no effect on survival, however, 111 In-labeled Match oligonucleotides significantly reduced clonogenic survival and upregulated the DNA damage marker gH2AX. Minimal radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to 111 In-Match oligonucleotides. Match oligonucleotides localized in close proximity to nuclear Cajal bodies in telomerasepositive cells. In comparison with Match oligonucleotides, 111 In-Scramble or 111 In-Mismatch oligonucleotides demonstrated reduced retention and negligible impact on cell survival. This study indicates the therapeutic activity of radiolabeled oligonucleotides that specifically target hTR through potent telomerase inhibition and DNA damage induction in telomerase-expressing cancer cells and paves the way for the development of novel oligonucleotide radiotherapeutics targeting telomerase-positive cancers. Significance: These findings present a novel radiolabeled oligonucleotide for targeting telomerase-positive cancer cells that exhibits dual activity by simultaneously inhibiting telomerase and promoting radiation-induced genomic DNA damage.

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“…Telomerase inhibitors such as Imetelstat, coupled with radiotherapy, enhanced the cancer cell response to irradiation via telomere dysfunction [268]. Inhibitors directly targeting telomeres, such as T-oligos, G-quadruplexes, telomestatin, G-quadruplex ligand, and shelterin proteins-TRF2, TPP1, and POT1, are also shown to improve radiosensitivity [268,269].…”

Section: Telomeres As Potential Targets For Anti-cancer Therapymentioning

confidence: 99%

Telomeres and Telomere Length: A General Overview

Srinivas

Rachakonda

Kumar

2020

Cancers

197

130

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Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.

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Targeting telomerase and telomeres to enhance ionizing radiation effects in in vitro and in vivo cancer models

Cited by 36 publications

References 203 publications

Naphthalene diimide‐derivatives G‐quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

Naphthalene diimide‐derivatives G‐quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells

Telomeres and Telomere Length: A General Overview

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