Chandrani Chattopadhyay, Janos Roszik, Rajat Bhattacharya, Md Alauddin, Iqbal Mahmud, Sirisha Yadugiri, Mir Mustafa Ali, Fatima S Khan, Varun Vijay Prabhu, Philip L Lorenzi, Bo Wei, Elizabeth Burton, Rohini R Morey, Rossana Lazcano, Michael A Davies, Sapna P Patel, Elizabeth A Grimm
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引用次数: 0
摘要
背景：葡萄膜黑色素瘤（UM）是一种侵袭性很强的疾病，治疗方法很少。我们以前曾证实，黑色素瘤以高氧化磷酸化（OXPHOS）为特征。在此，我们测试了亚胺培南的抗肿瘤、信号传导和新陈代谢作用，亚胺培南是CLPP激活剂，可间接抑制OXPHOS，并已证明对患者安全：我们评估了 UM 患者样本中 CLPP 的表达。我们测试了亚胺培南（ONC201 和 ONC212）对 UM 细胞系体外生长、存活、信号传导和代谢的影响，以及对 UM 肝转移模型体内治疗效果的影响：结果：在原发性 UM 和 mUM 患者样本中检测到了 CLPP 的表达。ONC201和ONC212可减少OXPHOS效应因子，抑制细胞生长和迁移，并诱导体外人类UM细胞株凋亡。ONC212 可抑制 OXPHOS、增加代谢压力和凋亡途径、抑制氨基酸代谢并诱导细胞死亡相关脂质。在两种 UM 肝转移模型中，ONC212 还能减少肿瘤负荷，提高体内存活率：结论：咪啶酮类药物是一种很有前景的策略，可用于对荨麻疹的进一步测试和开发。
Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.
Background: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients.
Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models.
Results: CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models.
Conclusions: Imipridones are a promising strategy for further testing and development in mUM.
期刊介绍：
The British Journal of Cancer is one of the most-cited general cancer journals, publishing significant advances in translational and clinical cancer research.It also publishes high-quality reviews and thought-provoking comment on all aspects of cancer prevention,diagnosis and treatment.
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