Improving neuroblastoma therapy with a new p53 family-activating agent

Neuroblastoma (NB) is among the most common malignancies in children and represents a therapeutic challenge in pediatric oncology. p53 family proteins play a critical role in protecting cells from genomic instability and malignant transformation. However, in NB, their activities are often inhibited by interacting proteins such as MDM2. The interplay between p53 family pathway and N-Myc, a key biomarker of poor prognosis, is also a critical factor in NB pathogenesis. Herein, we disclose 1-(dibromomethyl)-3,4,6-trimethoxy-9 H -xanthen-9-one (LEM3) as a new p53 family-activating agent with potent NB anticancer activity. At 0.13-2.1 μM, LEM3 inhibited the growth of several NB cell lines. Its activity was further evidenced in spheroids, patient-derived NB cells , and in a vasculature stiffness-based model of MYCN -amplified NB cells. This growth-inhibitory effect was associated with cell cycle arrest and apoptosis, in SH-SY5Y and SK-N-BE(2) NB cells, without apparent acquisition of resistance. LEM3 inhibited cell migration and invasion and reduced the expression of NB-related prognostic markers, particularly MYCN mRNA and protein levels. LEM3 released p53, TAp63, and TAp73 from their interaction with MDM2 both in a yeast-based assay and NB cells; for p53, this led to increased protein stabilization, DNA-binding ability, and transcriptional activity. Fluorescence quenching and docking analyses suggested that LEM3 binds to p53, TAp63, and TAp73 at the MDM2-binding site within their transactivation domain. LEM3 also synergies with doxorubicin and cisplatin in NB cells. Given the central role of the p53 family-MDM2- MYCN axis in NB pathogenesis, our findings support LEM3 as a promising compound for advancing NB targeted therapy.

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Publication Details

Journal
European Journal of Pharmacology
Published
2025-10-24
DOI
https://doi.org/10.1016/j.ejphar.2025.178295
Primary Topic
Neuroblastoma Research and Treatments
Type
article
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article

Improving neuroblastoma therapy with a new p53 family-activating agent

Veronica Zingales, Amos Hong Pheng Loh, Cláudia Nunes, Catherine Murphy et al.
European Journal of Pharmacology
Neuroblastoma Research and Treatments
article

Improving neuroblastoma therapy with a new p53 family-activating agent

Veronica Zingales, Amos Hong Pheng Loh, Cláudia Nunes, Catherine Murphy, Salette Reis, J. Škoda, Alberto Inga, Emı́lia Sousa, Aránzazu Villasante, Eduarda P. Martins, Diana I. S. P. Resende, Lucı́lia Saraiva, Josep Samitier, Bruno R. da Costa, Rita de Fátima da Silva, Francesca Broso, Andreia Palmeira, Paula de Oliveira, Joana Almeida, Julia R. Ferreira, Aiswariya Vadivellu
article en

Abstract

Neuroblastoma (NB) is among the most common malignancies in children and represents a therapeutic challenge in pediatric oncology. p53 family proteins play a critical role in protecting cells from genomic instability and malignant transformation. However, in NB, their activities are often inhibited by interacting proteins such as MDM2. The interplay between p53 family pathway and N-Myc, a key biomarker of poor prognosis, is also a critical factor in NB pathogenesis. Herein, we disclose 1-(dibromomethyl)-3,4,6-trimethoxy-9 H -xanthen-9-one (LEM3) as a new p53 family-activating agent with potent NB anticancer activity. At 0.13-2.1 μM, LEM3 inhibited the growth of several NB cell lines. Its activity was further evidenced in spheroids, patient-derived NB cells , and in a vasculature stiffness-based model of MYCN -amplified NB cells. This growth-inhibitory effect was associated with cell cycle arrest and apoptosis, in SH-SY5Y and SK-N-BE(2) NB cells, without apparent acquisition of resistance. LEM3 inhibited cell migration and invasion and reduced the expression of NB-related prognostic markers, particularly MYCN mRNA and protein levels. LEM3 released p53, TAp63, and TAp73 from their interaction with MDM2 both in a yeast-based assay and NB cells; for p53, this led to increased protein stabilization, DNA-binding ability, and transcriptional activity. Fluorescence quenching and docking analyses suggested that LEM3 binds to p53, TAp63, and TAp73 at the MDM2-binding site within their transactivation domain. LEM3 also synergies with doxorubicin and cisplatin in NB cells. Given the central role of the p53 family-MDM2- MYCN axis in NB pathogenesis, our findings support LEM3 as a promising compound for advancing NB targeted therapy.

European Journal of PharmacologyVol. 1007
Universitat de València (ES), Universidade do Porto (PT), University of Trento (IT), Masaryk University (CZ), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES), KK Women's and Children's Hospital (SG), International Clinical Research Center, St. Anne's University Hospital Brno (CZ), Rede de Química e Tecnologia (PT), Institute for Bioengineering of Catalonia (ES), Città della Speranza Foundation (IT), Universitat de Barcelona (ES), University of Minho (PT)
Openalex Percentile: Top 56%
Neuroblastoma Research and Treatments
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