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

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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 p16INK4A and p14ARF, 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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Acknowledgments

MCP was supported by a research fellowship from Regione Campania (POR Campania FSE 2007–2013). The authors thank Prof Bruno Maresca (University of Salerno) for his critical review and dr. Chiara Piscopo (University of Salerno) for her technical support.

Funding

The work was supported by the Department of Pharmacy, University of Salerno, Italy.

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Authors and Affiliations

  1. Department of Pharmacy, University of Salerno, Fisciano, SA, Italy

    Maria Chiara Proto, Donatella Fiore, Giovanni Forte, Paola Cuozzo, Anna Ramunno, Patrizia Gazzerro, Maria Pascale & Silvia Franceschelli

  2. Department of Pharmacy, University of Naples “Federico II”, Naples, Italy

    Caterina Fattorusso

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  1. Maria Chiara Proto
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Contributions

MCP designed and conducted research, analyzed and interpreted data, wrote the paper. DF, GF, PC, performed research and analyzed data. AR, CF and MP supervised the project and gave substantial contribution to analysis and interpretation of data. PG and SF designed and supervised the project in its entirety, provided financial support, wrote and critically reviewed the paper. All authors approved the final version of the manuscript.

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Correspondence to Patrizia Gazzerro or Silvia Franceschelli.

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Maria Chiara Proto declares that she has no conflict of interest. Donatella Fiore declares that she has no conflict of interest. Giovanni Forte declares that he has no conflict of interest. Paola Cuozzo declares that she has no conflict of interest. Anna Ramunno declares that she has no conflict of interest. Caterina Fattorusso declares that she has no conflict of interest. Patrizia Gazzerro declares that she has no conflict of interest. Maria Pascale declares that she has no conflict of interest. Silvia Franceschelli declares that she has no conflict of interest.

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Proto, M.C., Fiore, D., Forte, G. et al. Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells. Invest New Drugs 38, 634–649 (2020). https://doi.org/10.1007/s10637-019-00813-4

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