Targeting neuroblastoma with a new inhibitor of the TAp73 interaction with MDM2 and mutant p53

Abstract

TAp73 is a key tumour suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumours with impaired p53 signalling, like neuroblastoma (NBL), TAp73 activation represents an encouraging strategy to suppress tumour growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumour activity independent of p53 expression. LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53 (mutp53), enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutp53-expressing tumor cells. By cellular thermal shift assay (CETSA), LEM2 induced thermal stabilization of TAp73α but not of MDM2 or mutp53, suggesting the potential interaction of LEM2 with TAp73α. Interestingly, neither LEM2 alcohol 1-(hydroxymethyl)-3,4-dimethoxy-9H-xanthen-9-one (LEMred) or carboxylic acid 3,4-dimethoxy-9-oxo-9H-xanthene-1-carboxylic acid (LEMox) derivatives were able to inhibit the TAp73-MDM2 interaction supporting that LEM2 biological activity was due to the molecule itself and not to its potential derivatives. Consistently with an activation of the TAp73 pathway, LEM2 also displayed potent antitumour activity against patient-derived NBL cells, both alone and in combination of with doxorubicin and cisplatin. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against NBL. Abstract