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.
- MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků MeSH
- buňky HT-29 MeSH
- cisplatina farmakologie MeSH
- doxorubicin farmakologie MeSH
- HCT116 buňky MeSH
- kontrolní body buněčného cyklu účinky léků MeSH
- lidé MeSH
- mutace MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- neuroblastom farmakoterapie genetika metabolismus patologie MeSH
- protein p73 genetika metabolismus MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie MeSH
- protoonkogenní proteiny c-mdm2 genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- signální transdukce účinky léků MeSH
- synergismus léků MeSH
- xantony farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
