Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells

Amato, Jussara; Miglietta, Giulia; Morigi, Rita; Iaccarino, Nunzia; Locatelli, Alessandra; Leoni, Alberto; Novellino, Ettore; Pagano, Bruno; Capranico, Giovanni; Randazzo, Antonio

doi:10.1021/acs.jmedchem.9b01866

Cited by 34 publications

(36 citation statements)

References 53 publications

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“…G-quadruplexes can also form where double-stranded DNA has been resolved to allow transcription to occur, a region known as an R-loop ( Figure 4 ) [ 61 , 180 ]. Conversely, stabilization of G-quadruplexes can increase the formation of R-loops at the same location [ 196 , 197 ]. Despite showing characteristics of heterochromatin, telomeres of humans and many other organisms are transcribed into telomeric repeat-containing RNA (TERRA) [ 198 , 199 ].…”

Section: G-quadruplexes In the Double-stranded Portion Of Telomerementioning

confidence: 99%

G-Quadruplexes at Telomeres: Friend or Foe?

Bryan

2020

Molecules

126

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Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures.

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Section: G-quadruplexes In the Double-stranded Portion Of Telomerementioning

confidence: 99%

G-Quadruplexes at Telomeres: Friend or Foe?

Bryan

2020

Molecules

126

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“…352,353 From a chemical biology point of view, R-loops thus represent another class of nucleic acid targets to damage DNA, an approach that has thus far only been attempted indirectly as no R-loop ligands are yet reported. For instance, R-loop formation was promoted by impeding canonical RNA maturation and spliceosome assembly 353,354 using the TOP1 inhibitor diospyrin D1, 355 or by stabilising G4 with PDS 356 and monohydrazone derivatives, 357 since stabilised G4s promote the formation of R-loops at transcribed genes and the reciprocal G4/R-loop stabilisation can arrest polymerases and trigger DSBs accumulation.…”

Section: Non-b Dna Structuresmentioning

confidence: 99%

DNA folds threaten genetic stability and can be leveraged for chemotherapy

et al. 2021

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“…Although, evidence for NPM1 role in multiple aspects of ribosome biogenesis is substantial, its redistribution and induced nucleolar stress in response to DNA damage response (DDR) have emerged recently 67 . Moreover, an intriguing effect of GQ stabilizing ligand is to induce DNA damage and genome instability 60 , 68 .…”

Section: Resultsmentioning

confidence: 99%

Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics

et al. 2020

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The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics. Methods: Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. In cellulo studies including DNA damage and oxidative stress evaluation guided us to perform in vitro (3D spheroid) and in vivo (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18. Results: Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway. Conclusion: Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former. In vivo therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.

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Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells

Cited by 34 publications

References 53 publications

G-Quadruplexes at Telomeres: Friend or Foe?

G-Quadruplexes at Telomeres: Friend or Foe?

DNA folds threaten genetic stability and can be leveraged for chemotherapy

Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics

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