Preclinical Evaluation of panobinostat and ONC201 for the treatment of diffuse intrinsic pontine glioma (DIPG)
Preclinical Evaluation of panobinostat and ONC201 for the treatment of diffuse intrinsic pontine glioma (DIPG)
复制标题
帕比司他和 ONC201 治疗弥漫性脑桥胶质瘤 (DIPG) 的临床前评价
DOI：
10.1016/j.dscb.2023.100113
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Bentayebi K
中科院分区：
文献类型：
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作者：
Bentayebi K
弥漫性桥脑胶质瘤(DIPG)又称儿科高级别胶质瘤(PHGG)，是一种生长迅速、侵袭性强的儿童脑癌。最近对DIPG分子发病机制的研究发现了新的治疗靶点，为开发以HDAC抑制剂为主的新药铺平了道路。然而，尽管进行了多年的试验，但尚未产生重大成果。Panobinostat是一种HDAC抑制剂，在DIPG中显示出有希望的临床前细胞毒性，但到目前为止在临床试验中失败了。本研究旨在重新评估Panobinostat在DIPG中对直接从患者获得的患者来源的DIPG细胞培养的有效性。ONC201是治疗DIPG的另一种潜在有效药物。这种凋亡剂已被考虑用于包括DIPG在内的几个弥漫性胶质瘤的临床试验。我们的结果揭示了DIPG细胞对帕诺比妥和ONC201的剂量依赖性反应。然而，与ONC201相比，Panobinostat在较低浓度时导致细胞存活率的平均百分比显著降低。当浓度大于或等于0.002μM时，细胞存活率显著降低(p<；0.05)，在0.1nμM后达到平台期，细胞存活率降至32.81±0.25%(p=66.74E−06)。ONC201仅在浓度等于或高于0.01gμM时才显著诱导细胞凋亡(p<；0.05)，其作用在0.2gμM后稳定。这项临床前研究支持与ONC201相比，Panobinostat作为一种潜在的治疗药物的有效性，没有观察到明显的协同作用。
Diffuse intrinsic pontine glioma (DIPG) also referred as paediatric high-grade glioma (pHGG) is a fast-growing and aggressive type of childhood brain cancer. Recent studies investigating the molecular pathogenesis of DIPG have identified new therapeutic targets, paving the way for a new line of drugs mainly HDAC inhibitors. However, despite long years of trials, no significant results have been generated yet. Panobinostat is a HDAC inhibitor that has shown promising preclinical cytotoxicity in DIPG but failed so far in clinical trials. This study aims to re-evaluate the efficacy of Panobinostat in DIPGin vitrousing patient-derived DIPG cell cultures obtained directly from patients. ONC201 is another potentially effective drug in DIPG. This apoptotic agent has been considered in a few clinical trials in diffuse glioma including DIPG. Our results reveal a dose-dependent response to Panobinostat and ONC201 in DIPG cells. However, Panobinostat caused a significant reduction in the mean percentage cell viability at a lower concentration compared to ONC201. Panobinostat caused significant decreases in DIPG cell viability at concentrations greater than or equal to 0.002 μM (p<0.05), the response reached a plateau after 0.1 μM, which reduced cell viability to 32.81 % ± 0.25 % (p= 6.74E−06) when compared to control cells. ONC201 only significantly induced apoptosis at concentrations equal or higher than 0.01 μM (p<0.05), with its effect plateauing after 0.2 μM. This pre-clinical study supports the effectiveness of Panobinostat as a potential therapeutic agent for DIPG compared to ONC201, with no apparent synergistic effect observed in combination.