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

Sara Gomes, Liliana Raimundo, Joana Soares, Joana B. Loureiro, Mariana Leão, Helena Ramos, Madalena N. Monteiro, Agostinho Lemos, Joana Moreira, Madalena Pinto, Petr Chlapek, Renata Veselska, Emília Sousa, Lucília Saraiva

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)90-102
Number of pages13
JournalCancer Letters
Volume446
Early online date19 Jan 2019
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • Anticancer therapy
  • Carbaldehydic xanthone
  • p73

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