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

In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives,8  g,8  h and8i, in melanoma cell lines, and we compared the effects of the most active of these, the8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that8i potentiates the inhibitory effect of Nutlin 3 and the combined use of8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the8i 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 the8i 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.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research