New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma. (1st April 2019)

• Record Type: Journal Article
• Authors: Gomes, Sara; Raimundo, Liliana; Soares, Joana; Loureiro, Joana B.; Leão, Mariana; Ramos, Helena; Monteiro, Madalena N.; Lemos, Agostinho; Moreira, Joana; Pinto, Madalena; Chlapek, Petr; Veselska, Renata; Sousa, Emília; Saraiva, Lucília
• Is Part Of: Cancer letters. Volume 446(2019)
• Page Start: 90
• Page End: 102
• Publication Date: 2019-04-01
• Subjects: p73 -- Carbaldehydic xanthone -- Anticancer therapy; CETSA cellular thermal shift assay -- CFU colony-forming unit -- CI combination index -- Co-IP co-immunoprecipitation -- DOXO doxorubicin -- DRI dose reduction index -- ETOP etoposide -- MDM murine double minute -- MTT 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide -- mut mutant -- NBL neuroblastoma -- SRB sulforhodamine B -- wt wild-type -- VEGF vascular endothelial growth factor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.01.014
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: LEM2 displays potent TAp73-dependent growth inhibitory effect on human tumor cells. LEM2 activates TAp73 through disruption of its interaction with MDM2 and mutant p53. LEM2 sensitizes neuroblastoma cells to the effect of current chemotherapeutics. LEM2 reveals potential clinical applications in neuroblastoma therapy.