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01-06-2020 | Melanoma | PRECLINICAL STUDIES

Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells

Authors: Maria Chiara Proto, Donatella Fiore, Giovanni Forte, Paola Cuozzo, Anna Ramunno, Caterina Fattorusso, Patrizia Gazzerro, Maria Pascale, Silvia Franceschelli

Published in: Investigational New Drugs | Issue 3/2020

Summary

Cutaneous melanoma, the most aggressive form of skin cancer, is characterized by activating BRAF mutations. Despite the initial success of selective BRAF inhibitors, only few patients exhibited complete responses, whereas many showed disease progression. Melanoma is one of the few types of cancer in which p53 is not frequently mutated, but p53 inactivation can be indirectly achieved by a stable activation of MDM2 induced by a deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) locus, encoding for p16^INK4A and p14^ARF, two tumor suppressor genes. In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives, 8 g, 8 h and 8i, in melanoma cell lines, and we compared the effects of the most active of these, the 8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that 8i potentiates the inhibitory effect of Nutlin 3 and the combined use of 8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the 8i compound reduces p53-MDM2 interaction and induces p53-HSP90 complex formation, suggesting that the observed raise in p53 transcriptional activity could be mediated by HSP90. Because the main feature of melanoma is the resistance to most chemotherapeutics, our studies suggest that the 8i tetra-substituted pyrrole derivative, restoring p53 functions and its transcriptional activities, may have potential application, at least as adjuvant, in the treatment of human melanoma.

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Title: Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells
Authors: Maria Chiara Proto
Donatella Fiore
Giovanni Forte
Paola Cuozzo
Anna Ramunno
Caterina Fattorusso
Patrizia Gazzerro
Maria Pascale
Silvia Franceschelli
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Melanoma
Melanoma
Published in: Investigational New Drugs / Issue 3/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00813-4

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