Hirayama Masahiro, Yamada Eri, Aoki Hiromasa, Izumi Kazuya, Amano Ayumi, Toriuchi Kohki, Ogami Koichi, Nagasaka Mai, Inoue Yasumichi, Hayashi Hidetoshi, Takeshita Satoru, Kakita Hiroki, Yamada Yasumasa, Aoyama Mineyoshi
Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan.
Division of Molecular Oncology, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Sci Rep. 2025 Jul 2;15(1):22917. doi: 10.1038/s41598-025-06922-w.
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.
BMI1是多梳抑制复合物1的一个组成部分，在包括神经母细胞瘤在内的多种癌症中过表达，凸显了其作为癌症治疗靶点的潜力。鉴于BMI1的关键作用，已合成了多种抑制剂并在一系列癌症中评估其治疗效果。在我们目前的研究中，BMI1抑制剂PTC - 028和PTC - 209对MYCN扩增的神经母细胞瘤表现出选择性抗肿瘤活性。值得注意的是，PTC - 028在较低浓度下具有毒性，可引发神经母细胞瘤细胞凋亡并诱导G1期积累，同时S期和G2/M期细胞群体减少，从而促进细胞周期停滞。全面的RNA测序分析表明，PTC - 028处理激活了p53信号通路，表明其在凋亡诱导机制中起关键作用。此外，PTC - 028处理导致抗凋亡蛋白水平降低，包括BCL2和MCL1。重要的是，PTC - 028在人神经母细胞瘤的小鼠异种移植模型中也表现出抗肿瘤疗效。这些结果表明，BMI1抑制剂，尤其是PTC - 028，是治疗侵袭性MYCN扩增神经母细胞瘤的有前景的治疗药物。
