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.

CIIMAR Laboratório de Química Orgânica e Farmacêutica Departamento de Ciências Químicas Faculdade de Farmácia Universidade do Porto Rua de Jorge Viterbo Ferreira n ° 228 4050 313 Porto Portugal

Laboratory of Tumor Biology Department of Experimental Biology Faculty of Science Masaryk University 61137 Brno Czech Republic; International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic

LAQV REQUIMTE Laboratório de Microbiologia Departamento de Ciências Biológicas Faculdade de Farmácia Universidade do Porto Rua de Jorge Viterbo Ferreira n ° 228 4050 313 Porto Portugal

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Deciphering the Role of p53 and TAp73 in Neuroblastoma: From Pathogenesis to Treatment