New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma

• Tipo: Artigo em Revista Científica Internacional
• Data: 2019

Autores

Gomes, S (Autor) Outra; Raimundo, L (Autor) Outra; Soares, J (Autor) Outra; Loureiro, JB (Autor) Outra; Leao, M (Autor) Outra; Ramos, H (Autor) Outra; Monteiro, MN (Autor) Outra; Lemos, A (Autor) Outra; Moreira, J (Autor) Outra; Pinto, M (Autor) Outra; Chlapek, P (Autor) Outra; Veselska, R (Autor) Outra; Emilia Sousa (Autor) FFUP; Lucilia Saraiva (Autor) FFUP

Revista

Título: Cancer Letters

Vol. 446

Páginas: 90-102

ISSN: 0304-3835

Editora: Elsevier

Indexação

ISI Web of Knowledge - 23 Citações

Scopus - 23 Citações

Outras Informações

ID Authenticus: P-00Q-92B

DOI: 10.1016/j.canlet.2019.01.014

Abstract (EN): TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 13