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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月2日

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  • Masahiro Hirayama,
  • Eri Yamada,
  • Hiromasa Aoki,
  • Kazuya Izumi,
  • Ayumi Amano,
  • Kohki Toriuchi,
  • Koichi Ogami,
  • Mai Nagasaka,
  • Yasumichi Inoue,
  • Hidetoshi Hayashi,
  • Satoru Takeshita,
  • Hiroki Kakita,
  • Yasumasa Yamada,
  • Mineyoshi Aoyama

摘要

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.