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Dive into the research topics where Angela Rizzo is active.

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Featured researches published by Angela Rizzo.


Journal of Clinical Investigation | 2007

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Erica Salvati; Carlo Leonetti; Angela Rizzo; Marco Scarsella; Marcella Mottolese; Rossella Galati; Isabella Sperduti; Malcolm F. G. Stevens; Maurizio D'Incalci; Maria A. Blasco; Giovanna Chiorino; Serge Bauwens; Béatrice Horard; Eric Gilson; Antonella Stoppacciaro; Gabriella Zupi; Annamaria Biroccio

Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors gamma-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.


Nucleic Acids Research | 2009

Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway.

Angela Rizzo; Erica Salvati; Manuela Porru; Carmen D’Angelo; Malcolm F. G. Stevens; Maurizio D’Incalci; Carlo Leonetti; Eric Gilson; Gabriella Zupi; Annamaria Biroccio

Functional telomeres are required to maintain the replicative ability of cancer cells and represent putative targets for G-quadruplex (G4) ligands. Here, we show that the pentacyclic acridinium salt RHPS4, one of the most effective and selective G4 ligands, triggers damages in cells traversing S phase by interfering with telomere replication. Indeed, we found that RHPS4 markedly reduced BrdU incorporation at telomeres and altered the dynamic association of the telomeric proteins TRF1, TRF2 and POT1, leading to chromosome aberrations such as telomere fusions and telomere doublets. Analysis of the molecular damage pathway revealed that RHPS4 induced an ATR-dependent ATM signaling that plays a functional role in the cellular response to RHPS4 treatment. We propose that RHPS4, by stabilizing G4 DNA at telomeres, impairs fork progression and/or telomere processing resulting in telomere dysfunction and activation of a replication stress response pathway. The detailed understanding of the molecular mode of action of this class of compounds makes them attractive tools to understand telomere biology and provides the basis for a rational use of G4 ligands for the therapy of cancer.


Oncogene | 2010

PARP1 is activated at telomeres upon G4 stabilization: Possible target for telomere-based therapy

Erica Salvati; Marco Scarsella; Manuela Porru; Angela Rizzo; Sara Iachettini; Lucio Tentori; Grazia Graziani; Maurizio D'Incalci; Malcolm F. G. Stevens; Augusto Orlandi; Daniela Passeri; Eric Gilson; Gabriella Zupi; Carlo Leonetti; Annamaria Biroccio

New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.


Nature Cell Biology | 2013

TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

Annamaria Biroccio; Julien Cherfils-Vicini; Adeline Augereau; Sébastien Pinte; Serge Bauwens; Jing Ye; Thomas Simonet; Béatrice Horard; Karine Jamet; Ludovic Cervera; Aaron Mendez-Bermudez; Delphine Poncet; Renée Grataroli; Claire T Kint De Rodenbeeke; Erica Salvati; Angela Rizzo; Pasquale Zizza; Michelle Ricoul; Céline Cognet; Thomas Kuilman; Helene Duret; Florian Lepinasse; Jacqueline Marvel; Els Verhoeyen; François-Loïc Cosset; Daniel S. Peeper; Mark J. Smyth; Arturo Londoño-Vallejo; Laure Sabatier; Vincent Picco

Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4—a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4—was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity.


Journal of Medicinal Chemistry | 2011

N-cyclic bay-substituted perylene G-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage.

Casagrande; Erica Salvati; Antonello Alvino; Armandodoriano Bianco; A Ciammaichella; Carmen D'Angelo; L Ginnari-Satriani; Am Serrilli; Sara Iachettini; Carlo Leonetti; Stephen Neidle; Giancarlo Ortaggi; Manuela Porru; Angela Rizzo; Marco Franceschin; Annamaria Biroccio

A series of bay-substituted perylene derivatives is reported as a new class of G-quadruplex ligands. The synthesized compounds have differing N-cyclic substituents on the bay area and differing side chains on the perylene major axis. ESI-MS and FRET measurements highlighted the strongest quadruplex binders in this series and those showing the highest quadruplex/duplex selectivity. Several biological assays were performed on these compounds, which showed that compound 5 (PPL3C) triggered a DNA damage response in transformed cells with the formation of telomeric foci containing phosphorylated γ-H2AX and 53BP1. This effect mainly occurred in replicating cells and was consistent with Pot1 dissociation. Compound 5 does not induce telomere damage in normal cells, which are unaffected by treatment with the compound, suggesting that this agent preferentially kills cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs.


Journal of Medicinal Chemistry | 2012

Shooting for Selective Druglike G‑Quadruplex Binders: Evidence for Telomeric DNA Damage and Tumor Cell Death

Sandro Cosconati; Angela Rizzo; Roberta Trotta; Bruno Pagano; Sara Iachettini; Stefano De Tito; Ilaria Lauri; Iolanda Fotticchia; Mariateresa Giustiniano; Luciana Marinelli; Concetta Giancola; Ettore Novellino; Annamaria Biroccio; Antonio Randazzo

Targeting of DNA secondary structures, such as G-quadruplexes, is now considered an appealing opportunity for drug intervention in anticancer therapy. So far, efforts made in the discovery of chemotypes able to target G-quadruplexes mainly succeeded in the identification of a number of polyaromatic compounds featuring end-stacking binding properties. Against this general trend, we were persuaded that the G-quadruplex grooves can recognize molecular entities with better drug-like and selectivity properties. From this idea, a set of small molecules was identified and the structural features responsible for G-quadruplex recognition were delineated. These compounds were demonstrated to have enhanced affinity and selectivity for the G-quadruplex over the duplex structure. Their ability to induce selective DNA damage at telomeric level and to induction of apoptosis and senescence on tumor cells is herein experimentally proven.


ChemMedChem | 2012

Aromatic Core Extension in the Series of N‐Cyclic Bay‐Substituted Perylene G‐Quadruplex Ligands: Increased Telomere Damage, Antitumor Activity, and Strong Selectivity for Neoplastic over Healthy Cells

Marco Franceschin; Angela Rizzo; Valentina Casagrande; Erica Salvati; Antonello Alvino; Alessandro Altieri; Alina Ciammaichella; Sara Iachettini; Carlo Leonetti; Giancarlo Ortaggi; Manuela Porru; Armandodoriano Bianco; Annamaria Biroccio

Based on previous work on both perylene and coronene derivatives as G‐quadruplex binders, a novel chimeric compound was designed: N,N′‐bis[2‐(1‐piperidino)‐ethyl]‐1‐(1‐piperidinyl)‐6‐[2‐(1‐piperidino)‐ethyl]‐benzo[ghi]perylene‐3,4:9,10‐tetracarboxylic diimide (EMICORON), having one piperidinyl group bound to the perylene bay area (positions 1, 12 and 6, 7 of the aromatic core), sufficient to guarantee good selectivity, and an extended aromatic core able to increase the stacking interactions with the terminal tetrad of the G‐quadruplex. The obtained “chimera” molecule, EMICORON, rapidly triggers extensive DNA damage of telomeres, associated with the delocalization of telomeric protein protection of telomeres 1 (POT1), and efficiently limits the growth of both telomerase‐positive and ‐negative tumor cells. Notably, the biological effects of EMICORON are more potent than those of the previously described perylene derivative (PPL3C), and more interestingly, EMICORON appears to be detrimental to transformed and tumor cells, while normal fibroblasts expressing telomerase remain unaffected. These results identify a new promising G‐quadruplex ligand, structurally and biologically similar on one side to coronene and on the other side to a bay‐monosubstituted perylene, that warrants further studies.


Journal of Cellular Physiology | 2010

Inhibition of PARP activity by PJ-34 leads to growth impairment and cell death associated with aberrant mitotic pattern and nucleolar actin accumulation in M14 melanoma cell line

Marta Chevanne; Michele Zampieri; Riccardo Caldini; Angela Rizzo; Fabio Ciccarone; Angela Catizone; Carmen D'Angelo; Tiziana Guastafierro; Anna Biroccio; Anna Reale; Gabriella Zupi; Paola Caiafa

The capability of PARP activity inhibitors to prevent DNA damage recovery suggested the use of these drugs as chemo‐ and radio‐sensitisers for cancer therapy. Our research, carried out on cultured human M14 melanoma cells, was aimed to examine if PJ‐34, a potent PARP activity inhibitor of second generation, was per se able to affect the viability of these cancer cells without any DNA damaging agents. Using time‐lapse videomicroscopy, we evidenced that 10 µM PJ‐34 treatment induced severe mitotic defects leading to dramatic reduction of cell proliferation and to cell death. PJ‐34 cytotoxic effect was further confirmed by analysis of cell viability and clonogenic assay. Absence of canonic apoptosis markers allowed us to exclude this kind of cell death. No single and/or double stranded DNA damage was evidenced. Immunofluorescence analysis showed an aberrant mitotic scenario in several cells and subsequent multinucleation suggesting an atypical way for cells to die: the mitotic catastrophe. The detection of aberrant accumulation of polymerised actin inside the nucleolus was noteworthy. Taken toghether, our results demonstrate that, targeting PARP activity by PJ‐34, cancer cell survival is affected independently of DNA damage repair. Two findings are remarkable: (a) cisplatin concentration can be reduced by three quarters if it is followed by treatment with 10 µM PJ‐34 for 24 h to obtain the same citotoxic effect; (b) effects dependent on PJ‐34 treatment are reversible. Our data suggest that, to reduce the harm done to non‐tumour cells during chemotherapy with cisplatin, the latter could be coupled with PJ‐34 treatment. J. Cell. Physiol. 222: 401–410, 2010.


Journal of Experimental & Clinical Cancer Research | 2013

On and off-target effects of telomere uncapping G-quadruplex selective ligands based on pentacyclic acridinium salts

Sara Iachettini; Malcolm F. G. Stevens; Mark Frigerio; Marc Geoffery Hummersone; Ian Hutchinson; Thomas P. Garner; Mark S. Searle; David Wilson; Manoj Munde; Rupesh Nanjunda; Carmen D’Angelo; Pasquale Zizza; Angela Rizzo; Chiara Cingolani; Federica De Cicco; Manuela Porru; Maurizio D’Incalci; Carlo Leonetti; Annamaria Biroccio; Erica Salvati

Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment.The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant β2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay.Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with β2 adrenergic receptor, and do not significatively inhibit the hERG tail current while demonstrating potent telomere on-target properties comparing closely with 1. Of the two isomers, the 2-acetyl-aminopentacycle (2) more closely mimics the overall biological profile of 1 and this information will be used to guide further synthetic efforts to identify novel variants of this chemotype, to maximize on-target and minimize off-target activities.Consequently, the improvement of toxicological profile of these compounds could therefore lead to the obtainment of suitable molecules for clinical development offering new pharmacological strategies in cancer treatment.


Nucleic Acids Research | 2016

Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance

Pasquale Zizza; Chiara Cingolani; Simona Artuso; Erica Salvati; Angela Rizzo; Carmen D'Angelo; Manuela Porru; Bruno Pagano; Jussara Amato; Antonio Randazzo; Ettore Novellino; Antonella Stoppacciaro; Eric Gilson; Giorgio Stassi; Carlo Leonetti; Annamaria Biroccio

Cancer stem cells (CSCs) have been identified in several solid malignancies and are now emerging as a plausible target for drug discovery. Beside the questionable existence of CSCs specific markers, the expression of CD133 was reported to be responsible for conferring CSC aggressiveness. Here, we identified two G-rich sequences localized within the introns 3 and 7 of the CD133 gene able to form G-quadruplex (G4) structures, bound and stabilized by small molecules. We further showed that treatment of patient-derived colon CSCs with G4-interacting agents triggers alternative splicing that dramatically impairs the expression of CD133. Interestingly, this is strongly associated with a loss of CSC properties, including self-renewing, motility, tumor initiation and metastases dissemination. Notably, the effects of G4 stabilization on some of these CSC properties are uncoupled from DNA damage response and are fully recapitulated by the selective interference of the CD133 expression. In conclusion, we provided the first proof of the existence of G4 structures within the CD133 gene that can be pharmacologically targeted to impair CSC aggressiveness. This discloses a class of potential antitumoral agents capable of targeting the CSC subpopulation within the tumoral bulk.

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Dive into the Angela Rizzo's collaboration.

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Annamaria Biroccio

École normale supérieure de Lyon

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Erica Salvati

École normale supérieure de Lyon

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Carlo Leonetti

École normale supérieure de Lyon

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Eric Gilson

École normale supérieure de Lyon

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Manuela Porru

École normale supérieure de Lyon

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Gabriella Zupi

École normale supérieure de Lyon

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Carmen D'Angelo

The Catholic University of America

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Ettore Novellino

University of Naples Federico II

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Antonio Randazzo

University of Naples Federico II

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