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

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Authors

GOMES Sara RAIMUNDO Liliana Sofia Gomes SOARES Joana LOUREIRO Joana B. LEAO Mariana NOGUEIRA RAMOS ROCHA Helena Isabel MONTEIRO Madalena N. LEMOS Agostinho MOREIRA Joana PINTO Madalena CHLAPEK Petr VESELSKÁ Renata SOUSA Emília SARAIVA Lucília

Year of publication 2019
Type Article in Periodical
Magazine / Source Cancer Letters
MU Faculty or unit

Faculty of Science

Citation
Web Full Text
Doi http://dx.doi.org/10.1016/j.canlet.2019.01.014
Keywords p73; Carbaldehydic xanthone; Anticancer therapy
Description 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.
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