Search

Your search keyword '"Piccarducci, R."' showing total 3 results
Start Over Author "Piccarducci, R." Topic glioblastoma
3 results on '"Piccarducci, R."'

1. CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme.

Author

Daniele S, La Pietra V, Piccarducci R, Pietrobono D, Cavallini C, D'Amore VM, Cerofolini L, Giuntini S, Russomanno P, Puxeddu M, Nalli M, Pedrini M, Fragai M, Luchinat C, Novellino E, Taliani S, La Regina G, Silvestri R, Martini C, and Marinelli L

Subjects
Brain Neoplasms enzymology, Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Drug Synergism, Glioblastoma enzymology, Glioblastoma genetics, Glioblastoma pathology, Humans, Neoplasm Invasiveness, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells enzymology, Neoplastic Stem Cells pathology, Neurogenesis drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Receptors, CXCR4 metabolism, Signal Transduction, Spheroids, Cellular, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzylamines pharmacology, Brain Neoplasms drug therapy, Cell Cycle Proteins antagonists & inhibitors, Cyclams pharmacology, Glioblastoma drug therapy, Indoles pharmacology, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Receptors, CXCR4 antagonists & inhibitors
Abstract

Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Published
2021
Full Text
View/download PDF

2. Simultaneous Targeting of RGD-Integrins and Dual Murine Double Minute Proteins in Glioblastoma Multiforme.

Author

Merlino F, Daniele S, La Pietra V, Di Maro S, Di Leva FS, Brancaccio D, Tomassi S, Giuntini S, Cerofolini L, Fragai M, Luchinat C, Reichart F, Cavallini C, Costa B, Piccarducci R, Taliani S, Da Settimo F, Martini C, Kessler H, Novellino E, and Marinelli L

Subjects
Animals, Cell Line, Tumor, Integrin alpha5beta1 antagonists & inhibitors, Integrin alphaVbeta3 antagonists & inhibitors, Mice, Models, Molecular, Peptidomimetics pharmacology, Protein Conformation, Proto-Oncogene Proteins c-mdm2 chemistry, Glioblastoma drug therapy, Glioblastoma metabolism, Integrin alpha5beta1 metabolism, Integrin alphaVbeta3 metabolism, Molecular Targeted Therapy methods, Oligopeptides chemistry, Proto-Oncogene Proteins c-mdm2 metabolism
Abstract

In the fight against Glioblastoma Multiforme, recent literature data have highlighted that integrin α5β1 and p53 are part of convergent pathways in the control of glioma apoptosis. This observation prompted us to seek a molecule able to simultaneously modulate both target families. Analyzing the results of a previous virtual screening against murine double minute 2 protein (MDM2), we envisaged that Arg-Gly-Asp (RGD)-mimetic molecules could be inhibitors of MDM2/4. Herein, we present the discovery of compound 7, which inhibits both MDM2/4 and α5β1/αvβ3 integrins. A lead optimization campaign was carried out on 7 with the aim to preserve the activities on integrins while improving those on MDM proteins. Compound 9 turned out to be a potent MDM2/4 and α5β1/αvβ3 blocker. In p53-wild type glioma cells, 9 arrested cell cycle and proliferation and strongly reduced cell invasiveness, emerging as the first molecule of a novel class of integrin/MDM inhibitors, which might be especially useful in subpopulations of patients with glioblastoma expressing a functional p53 concomitantly with a high level of α5β1 integrin.

Published
2018
Full Text
View/download PDF

3. CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme

Author

Claudia Martini, Valeria La Pietra, Romano Silvestri, Linda Cerofolini, Simona Daniele, Michela Puxeddu, Sabrina Taliani, Chiara Cavallini, Martina Pedrini, Stefano Giuntini, Marianna Nalli, Vincenzo Maria D'Amore, Luciana Marinelli, Marco Fragai, Claudio Luchinat, Ettore Novellino, Deborah Pietrobono, Rebecca Piccarducci, Giuseppe La Regina, Pasquale Russomanno, Daniele, S., La Pietra, V., Piccarducci, R., Pietrobono, D., Cavallini, C., D'Amore, V. M., Cerofolini, L., Giuntini, S., Russomanno, P., Puxeddu, M., Nalli, M., Pedrini, M., Fragai, M., Luchinat, C., Novellino, E., Taliani, S., La Regina, G., Silvestri, R., Martini, C., and Marinelli, L.

Subjects
0301 basic medicine, p53, Benzylamines, Indoles, Cell Cycle Proteins, Cyclams, CXCR4, Benzylamine, 0302 clinical medicine, Cell Movement, Cell Cycle Protein, Antineoplastic Combined Chemotherapy Protocols, Proto-Oncogene Protein, CXCR4 antagonist, biology, Chemistry, GBM stem-Like cells (GSCs), Brain Neoplasms, Drug Synergism, Proto-Oncogene Proteins c-mdm2, Cyclam, Neoplastic Stem Cells, Mdm2, Stem cell, Human, Signal Transduction, Receptors, CXCR4, Neurogenesis, Brain Neoplasm, 03 medical and health sciences, MDM4, Downregulation and upregulation, MDM2, Glioma, Neurosphere, Cell Line, Tumor, Proto-Oncogene Proteins, Spheroids, Cellular, medicine, Humans, Neoplasm Invasiveness, Cell Proliferation, Pharmacology, Neoplasm Invasivene, Glioblastoma multiforme (GBM), Antineoplastic Combined Chemotherapy Protocol, medicine.disease, 030104 developmental biology, Indole, Cancer cell, biology.protein, Cancer research, Neurogenesi, Neoplastic Stem Cell, Tumor Suppressor Protein p53, Glioblastoma, 030217 neurology & neurosurgery
Abstract

Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too.

Published
2020

Catalog

Books, media, physical & digital resources
See catalog results