Pharmacologic inhibition of BMI1 exerts antitumor effects against MYCN-amplified neuroblastoma, with activation of the p53 pathway

Sci Rep. 2025 Jul 2;15(1):22917. doi: 10.1038/s41598-025-06922-w.

Abstract

BMI1, a constituent of polycomb repressive complex 1, is overexpressed in a variety of cancers, including neuroblastoma, highlighting its potential as a target for cancer therapeutics. Given the pivotal role of BMI1, a number of inhibitors have been synthesized and assessed for therapeutic efficacy across a spectrum of cancers. In our present study, the BMI1 inhibitors PTC-028 and PTC-209 exhibited selective antitumor activity against MYCN-amplified neuroblastoma. Notably, PTC-028, which exhibited toxicity at lower concentrations, triggered apoptosis in neuroblastoma cells and induced G1-phase accumulation, along with reductions in S-phase and G2/M-phase populations, thereby promoting cell cycle arrest. Thorough RNA sequencing analyses revealed that PTC-028 treatment activated the p53 signaling pathway, suggesting it plays a critical role in the mechanism of apoptosis induction. Moreover, PTC-028 treatment led to decreases in levels of anti-apoptotic proteins, including BCL2 and MCL1. Significantly, PTC-028 also exhibited antitumor efficacy in a mouse xenograft model of human neuroblastoma. These results suggest that BMI1 inhibitors, particularly PTC-028, are promising therapeutic agents for the management of aggressive MYCN-amplified neuroblastomas.

Keywords: BMI1; MYCN; Neuroblastoma; PTC-028; p53.

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterocyclic Compounds, 2-Ring
  • Humans
  • Mice
  • N-Myc Proto-Oncogene Protein* / genetics
  • N-Myc Proto-Oncogene Protein* / metabolism
  • Neuroblastoma* / drug therapy
  • Neuroblastoma* / genetics
  • Neuroblastoma* / metabolism
  • Neuroblastoma* / pathology
  • Polycomb Repressive Complex 1* / antagonists & inhibitors
  • Polycomb Repressive Complex 1* / genetics
  • Polycomb Repressive Complex 1* / metabolism
  • Signal Transduction* / drug effects
  • Thiazoles
  • Tumor Suppressor Protein p53* / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Polycomb Repressive Complex 1
  • N-Myc Proto-Oncogene Protein
  • Tumor Suppressor Protein p53
  • BMI1 protein, human
  • MYCN protein, human
  • Antineoplastic Agents
  • PTC-209
  • Heterocyclic Compounds, 2-Ring
  • Thiazoles