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

Daniela Muoio, Francesco Berardinelli, Stefano Leone, Elisa Coluzzi, Alessandra di Masi, Filippo Doria, Mauro Freccero, Antonella Sgura, Marco Folini, Antonio Antoccia

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3769-3785
Number of pages17
JournalFEBS Journal
Volume285
Issue number20
DOIs
Publication statusPublished - Oct 2018

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G-Quadruplexes
Cell proliferation
Glioma
Cell Cycle
Cells
Cell Proliferation
Ligands
Derivatives
Telomere
Bromodeoxyuridine
Cell Cycle Checkpoints
S Phase
naphthalenediimide
Ionizing radiation
Glioblastoma
Ionizing Radiation
Oncogenes
DNA Repair
Histones
Tumors

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Naphthalene diimide-derivatives G-quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells. / Muoio, Daniela; Berardinelli, Francesco; Leone, Stefano; Coluzzi, Elisa; di Masi, Alessandra; Doria, Filippo; Freccero, Mauro; Sgura, Antonella; Folini, Marco; Antoccia, Antonio.

In: FEBS Journal, Vol. 285, No. 20, 10.2018, p. 3769-3785.

Research output: Contribution to journalArticle

Muoio, D, Berardinelli, F, Leone, S, Coluzzi, E, di Masi, A, Doria, F, Freccero, M, Sgura, A, Folini, M & Antoccia, A 2018, 'Naphthalene diimide-derivatives G-quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells', FEBS Journal, vol. 285, no. 20, pp. 3769-3785. https://doi.org/10.1111/febs.14628
Muoio, Daniela ; Berardinelli, Francesco ; Leone, Stefano ; Coluzzi, Elisa ; di Masi, Alessandra ; Doria, Filippo ; Freccero, Mauro ; Sgura, Antonella ; Folini, Marco ; Antoccia, Antonio. / Naphthalene diimide-derivatives G-quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells. In: FEBS Journal. 2018 ; Vol. 285, No. 20. pp. 3769-3785.
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T1 - Naphthalene diimide-derivatives G-quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

AU - Muoio, Daniela

AU - Berardinelli, Francesco

AU - Leone, Stefano

AU - Coluzzi, Elisa

AU - di Masi, Alessandra

AU - Doria, Filippo

AU - Freccero, Mauro

AU - Sgura, Antonella

AU - Folini, Marco

AU - Antoccia, Antonio

N1 - © 2018 Federation of European Biochemical Societies.

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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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DO - 10.1111/febs.14628

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SP - 3769

EP - 3785

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

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