NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
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DOI：
10.1038/s41419-019-2026-y
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发表时间：
2019-10-16
影响因子：
9
通讯作者：
Niklison-Chirou, Maria Victoria
中科院分区：
文献类型：
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作者：
Frisira, Eleni;Rashid, Fatima;Niklison-Chirou, Maria Victoria
髓母细胞瘤（MB）是最常见的恶性实体儿科脑肿瘤。MB的标准治疗是手术切除肿瘤、放疗和化疗。这种疗法与高发病率和不良副作用有关。因此，迫切需要更有针对性和毒性更小的治疗方法来改善幸存者的生活质量。NPI-0052是一种新型的蛋白酶体抑制剂，其不可逆地结合20 S蛋白酶体亚基。该化合物对转移性实体瘤、胶质母细胞瘤和多发性骨髓瘤具有抗肿瘤活性，并且具有良好的安全性。重要的是，NPI-0052具有亲脂性结构，可以穿透血脑屏障，使其成为脑肿瘤的合适治疗方法。在本研究中，我们进行了计算机基因表达分析，以评估MB中蛋白酶体亚基的表达。为了评估NPI-0052的抗癌活性，我们使用了一系列MB患者来源的MB细胞和细胞系。在源自患者来源的MB细胞的肿瘤类器官中评价NPI-0052与γ-辐射的协同细胞死亡。我们发现蛋白酶体亚单位的高表达是MB患者预后不良的因素。此外，我们的临床前工作表明，NPI-0052可以抑制MB细胞中的蛋白酶体活性并激活细胞凋亡。此外，我们观察到NPI-0052与γ-辐射（当前MB疗法的组分）具有协同凋亡作用。在这里，我们提出了令人信服的临床前证据表明，NPI-0052可用作p53家族表达MB肿瘤的辅助治疗。
Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are vitally needed to improve the quality of life of survivors. NPI-0052 is a novel proteasome inhibitor that irreversibly binds the 20S proteasome subunit. This compound has anti-tumour activity in metastatic solid tumours, glioblastoma and multiple myeloma with a good safety profile. Importantly, NPI-0052 has a lipophilic structure and can penetrate the blood-brain barrier, making it a suitable treatment for brain tumours. In the present study, we performed an in silico gene expression analysis to evaluate the proteasome subunit expression in MB. To evaluate the anticancer activity of NPI-0052, we used a range of MB patient-derived MB cells and cell lines. The synergistic cell death of NPI-0052 with y-radiation was evaluated in tumour organoids derived from patient-derived MB cells. We show that high expression of proteasome subunits is a poor prognostic factor for MB patients. Also, our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with gamma-radiation, a component of the current MB therapy. Here, we present compelling preclinical evidence that NPI-0052 can be used as an adjuvant treatment for p53-family-expressing MB tumours.