体外和计算研究哌罗嗪和哌罗嗪天冬氨酸作为潜在的抗胶质母细胞瘤多形性药物。
In Vitro and Computational Studies of Perezone and Perezone Angelate as Potential Anti-Glioblastoma Multiforme Agents.
机构信息
Laboratorio de Cultivo Celular, Escuela Superior de Medicina, IPN, Salvador Díaz Mirón esq. Plan de San Luis s/n, Casco de Santo Tomas, Miguel Hidalgo, Ciudad de Mexico 11340, Mexico.
Departamento de Ciencias Químicas, Facultad de Estudios Superiores Cuautitlán Campo 1, UNAM. Av. Primero de Mayo S/N, Sta María Guadalupe las Torres, Cuautitlán Izcalli 54740, Mexico.
出版信息
Molecules. 2022 Feb 26;27(5):1565. doi: 10.3390/molecules27051565.
Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, with a life expectancy of two years. It has been shown that Poly (ADP-ribose) polymerase 1 (PARP-1) protein is over-expressed in GBM cells, while its expression in healthy tissue is low. In addition, perezone, a phyto-compound, is a PARP-1 inhibitor with anti-neoplastic activity. As a consequence, in the present study, both in vitro and computational evaluations of perezone and its chemically related compound, perezone angelate, as anti-GBM agents were performed. Hence, the anti-proliferative assay showed that perezone angelate induces higher cytotoxicity in the GBM cell line (U373 IC = 6.44 μM) than perezone (U373 IC = 51.20 μM) by induction of apoptosis. In addition, perezone angelate showed low cytotoxic activity in rat glial cells (IC = 173.66 μM). PARP-1 inhibitory activity (IC = 5.25 μM) and oxidative stress induction by perezone angelate were corroborated employing in vitro studies. In the other hand, the performed docking studies allowed explaining the PARP-1 inhibitory activity of perezone angelate, and ADMET studies showed its probability to permeate cell membranes and the blood-brain barrier, which is an essential characteristic of drugs to treat neurological diseases. Finally, it is essential to highlight that the results confirm perezone angelate as a potential anti-GBM agent.
多形性胶质母细胞瘤（GBM）是最恶性的星形细胞瘤，患者的预期寿命为两年。研究表明，聚（ADP-核糖）聚合酶 1（PARP-1）蛋白在 GBM 细胞中过度表达，而在健康组织中的表达水平较低。此外，植物化合物派罗佐因是一种具有抗肿瘤活性的 PARP-1 抑制剂。因此，在本研究中，我们对派罗佐因及其化学相关化合物派罗佐因酯进行了体外和计算评估，以评估其作为抗 GBM 药物的潜力。因此，增殖抑制试验表明，派罗佐因酯通过诱导细胞凋亡，在 GBM 细胞系（U373 IC = 6.44 μM）中诱导的细胞毒性比派罗佐因（U373 IC = 51.20 μM）更高。此外，派罗佐因酯对大鼠神经胶质细胞的细胞毒性活性较低（IC = 173.66 μM）。体外研究证实了派罗佐因酯对 PARP-1 的抑制活性和诱导氧化应激作用。另一方面，进行的对接研究解释了派罗佐因酯对 PARP-1 的抑制活性，ADMET 研究表明其穿透细胞膜和血脑屏障的可能性，这是治疗神经疾病药物的一个重要特征。最后，值得强调的是，这些结果证实了派罗佐因酯作为一种有潜力的抗 GBM 药物。
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