Dottoressa di ricerca

ciclo: XXXIII

Titolo della tesi: Phenformin-mediated anti-tumor properties rely on a novel redox/corepressor interplay

The biguanides metformin and phenformin are antidiabetic drugs associated to well-established antitumor properties in preclinical and clinical settings. Despite intensive efforts and studies, the mechanism of action of biguanides in cancer is still unclear. The most accepted model links the effect of these drugs to their ability to inhibit Complex I of the mitochondrial electron transport chain, thereby decreasing respiration and causing energy stress and elevation of the redox state. However, this model has been questioned since inhibition of Complex I requires millimolar concentrations of biguanides and these values cannot be reached in patients and animal models, where the maximum tolerated doses are within the low micromolar range (i.e. 1-5 μM). Using Hedgehog-dependent Medulloblastoma (Shh MB) as a study model, we have demonstrated that therapeutic doses of phenformin do not inhibit Complex I but rather mitochondrial Glycerol-3-Phosphate Dehydrogenase (mGPD), a component of the glycerophosphate shuttle (GPS). This inhibition causes the increase of cytoplasmic redox state and NADH. We show that C-terminal Binding Protein 2 (CtBP2) senses the elevations of NADH and binds Gli1, the transcription factor and downstream effector of Hedgehog signaling, causing its functional inhibition and suppression of tumor growth. To understand whether this newly discovered mechanism is also effective in other types of malignancies, we studied the effect of biguanides on colorectal cancer (CRC) growth. As shown by our preliminary data, phenformin seems to inhibit cancer cell proliferation through a redox mechanism, mediated by the corepressor CtBP2 also in CRC. Notably, we observed that Free Fatty Acids (FFAs) act as redox-inducing nutrients as they significantly enhance the phenformin-induced NADH content and inhibition of cancer growth. Collectively, with our work we have discovered a previously uncharacterized mechanism of action of biguanides in cancer, whereby the mGPD-mediated elevation of redox state represents a key event, leading the subsequent corepressor-mediated inhibition of tumor growth. These results pave the way to new studies focused on the use of biguanides and/or other redox enhancing agents in cancer.

Produzione scientifica

11573/1684557 - 2023 - Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent
Nalli, Marianna; Di Magno, Laura; Wen, Yichao; Liu, Xin; D’Ambrosio, Michele; Puxeddu, Michela; Parisi, Anastasia; Sebastiani, Jessica; Sorato, Andrea; Coluccia, Antonio; Ripa, Silvia; Di Pastena, Fiorella; Capelli, Davide; Montanari, Roberta; Masci, Domiziana; Urbani, Andrea; Naro, Chiara; Sette, Claudio; Orlando, Viviana; D’Angelo, Sara; Biagioni, Stefano; Bigogno, Chiara; Dondio, Giulio; Pastore, Arianna; Stornaiuolo, Mariano; Canettieri, Gianluca; Liu, Te; Silvestri, Romano; La Regina, Giuseppe - 01a Articolo in rivista
rivista: ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE (Washington DC: American Chemical Society) pp. 1087-1103 - issn: 2575-9108 - wos: WOS:001022871100001 (0) - scopus: 2-s2.0-85164931909 (0)

11573/1660747 - 2022 - Discovery of novel human lactate dehydrogenase inhibitors: Structure-based virtual screening studies and biological assessment
Di Magno, L; Coluccia, A; Bufano, M; Ripa, S; La Regina, G; Nalli, M; Di Pastena, F; Canettieri, G; Silvestri, R; Frati, L - 01a Articolo in rivista
rivista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (Editions Scientifique & Medical Elsevier:23 Rue Linois, F 75724 Paris Cedex 15 France:011 33 1 71724646, INTERNET:, Fax: 011 33 1 71724664) pp. 114605- - issn: 0223-5234 - wos: WOS:000834164000003 (4) - scopus: 2-s2.0-85134696311 (4)

11573/1660745 - 2022 - The Mechanism of Action of Biguanides: New Answers to a Complex Question
Di Magno, L; Di Pastena, F; Bordone, R; Coni, S; Canettieri, G - 01g Articolo di rassegna (Review)
rivista: CANCERS (Basel: MDPI) pp. 3220- - issn: 2072-6694 - wos: WOS:000823881900001 (12) - scopus: 2-s2.0-85133129147 (12)

11573/1364966 - 2020 - Phenformin inhibits hedgehog-dependent tumor growth through a complex i-independent redox/corepressor module
Di Magno, L.; Manni, S.; Di Pastena, F.; Coni, S.; Macone, A.; Cairoli, S.; Sambucci, M.; Infante, P.; Moretti, M.; Petroni, M.; Nicoletti, C.; Capalbo, C.; De Smaele, E.; Di Marcotullio, L.; Giannini, G.; Battistini, L.; Goffredo, B. M.; Iorio, E.; Agostinelli, E.; Maroder, M.; Canettieri, G. - 01a Articolo in rivista
rivista: CELL REPORTS (Elsevier B.V. Cambridge MA: Cell Press) pp. 1735-1752 - issn: 2211-1247 - wos: WOS:000513920800008 (35) - scopus: 2-s2.0-85079335561 (35)

11573/1451071 - 2020 - Sulfonamide inhibitors of beta-catenin signaling as anticancer agents with different output on c-Myc
Di Magno, Laura; Di Pastena, Fiorella; Puxeddu, Michela; La Regina, Giuseppe; Coluccia, Antonio; Ciogli, Alessia; Manetto, Simone; Maroder, Marella; Canettieri, Gianluca; Silvestri, Romano; Nalli, Marianna - 01a Articolo in rivista
rivista: CHEMMEDCHEM (Weinheim : Wiley-VCH-Verl..) pp. 2264-2268 - issn: 1860-7179 - wos: WOS:000577594900001 (5) - scopus: 2-s2.0-85092511066 (5)

11573/1210601 - 2019 - Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation
Antonucci, Laura; Di Magno, Laura; D'amico, Davide; Manni, Simona; Serrao, Silvia Maria; Di Pastena, Fiorella; Bordone, Rosa; Yurtsever, Zuleyha Nihan; Caimano, Miriam; Petroni, Marialaura; Giorgi, Alessandra; Schininà, Maria Eugenia; Yates Iii, John R; Di Marcotullio, Lucia; De Smaele, Enrico; Checquolo, Saula; Capalbo, Carlo; Agostinelli, Enzo; Maroder, Marella; Coni, Sonia; Canettieri, Gianluca - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF ONCOLOGY (National Hellenic Research Foundation:48 Vas Constatinou Avenue, Athens 11635 Greece:011 30 1 7241505, Fax: 011 30 1 7241505Editore attuale:PROFESSOR D A SPANDIDOS, 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS, GREECE, 116 35. Editore precedente:Editorial Academy of the International Journal of Oncology.) pp. 505-514 - issn: 1019-6439 - wos: WOS:000454923900009 (25) - scopus: 2-s2.0-85058877986 (25)

11573/1223718 - 2019 - Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents
Coluccia, A.; La Regina, G.; Naccarato, V.; Nalli, M.; Orlando, V.; Biagioni, S.; De Angelis, M. L.; Baiocchi, M.; Gautier, C.; Gianni, S.; Di Pastena, F.; Di Magno, L.; Canettieri, G.; Coluccia, A. M. L.; Silvestri, R. - 01a Articolo in rivista
rivista: ACS MEDICINAL CHEMISTRY LETTERS (USA: ACS Publications) pp. 499-503 - issn: 1948-5875 - wos: WOS:000464767700019 (13) - scopus: 2-s2.0-85064264813 (13)

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