Kusaczuk Magdalena, Piskorz Wiktoria Monika, Domasik Julia
Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Mickiewicza 2A, Białystok, 15-222, Poland.
Pharmacol Rep. 2025 May 29. doi: 10.1007/s43440-025-00739-0.
Out of several types of tumors of the central nervous system (CNS), glioblastoma (GBM) represents one of the most frequent and malignant forms of brain neoplasms. To date, GBM holds very limited therapeutic options leaving patients with poor prognosis of survival. As such, novel treatment approaches are constantly quested. One of these strategies is based on the utilization of proteasome inhibitors (PIs). However, although several PIs have been approved as therapy for patients with hematological malignancies, these treatment benefits cannot not be easily extrapolated to brain tumors. This is mostly due to the blood-brain barrier (BBB) impermeability of the majority of PIs, which is then followed by their low brain bioavailability. Marizomib (MZB) is a unique, irreversible, second-generation proteasome inhibitor, which unlike other PIs can penetrate through the BBB, making it a promising therapeutic tool in brain tumors. Despite an indisputable therapeutic potential of MZB, it has yet failed to be successfully introduced to the clinics as a ready-to-use chemotherapy for GBM-suffering patients. Therefore, in this work we describe the potential of PIs as candidates for neuro-oncological drugs, present results of preclinical and clinical investigations concerning MZB in brain tumors, discuss possible reasons of failure of MZB-based therapies and delineate future directions of MZB-related studies.
在几种中枢神经系统（CNS）肿瘤中，胶质母细胞瘤（GBM）是最常见且恶性程度最高的脑肿瘤之一。迄今为止，GBM的治疗选择非常有限，患者的生存预后较差。因此，人们一直在探索新的治疗方法。其中一种策略是基于蛋白酶体抑制剂（PIs）的应用。然而，尽管几种PIs已被批准用于治疗血液系统恶性肿瘤患者，但这些治疗益处不易外推至脑肿瘤。这主要是由于大多数PIs不能透过血脑屏障（BBB），导致其在脑内的生物利用度较低。马里佐米布（MZB）是一种独特的、不可逆的第二代蛋白酶体抑制剂，与其他PIs不同，它可以穿透BBB，使其成为脑肿瘤治疗的一个有前景的工具。尽管MZB具有无可争议的治疗潜力，但它尚未成功作为一种现成的化疗药物应用于GBM患者的临床治疗。因此，在这项工作中，我们描述了PIs作为神经肿瘤药物候选物的潜力，展示了关于MZB在脑肿瘤中的临床前和临床研究结果，讨论了基于MZB的治疗失败的可能原因，并阐述了MZB相关研究的未来方向。
