Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug
Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug
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发现一种新型大黄酸-SAHA 杂合体作为多靶点抗胶质母细胞瘤药物
DOI：
10.1007/s10637-019-00821-4
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发表时间：
2020-06-01
影响因子：
3.4
通讯作者：
Pi, Rongbiao
中科院分区：
文献类型：
--
作者：
Chen, Jingkao;Luo, Bingling;Pi, Rongbiao
多形性胶质母细胞瘤（GBM）是中枢神经系统（CNS）最常见的恶性肿瘤。有效的治疗方法仍然有限。因此，迫切需要高效、不良反应少的新型化疗药物。组蛋白去乙酰化酶（HDAC）、血清和糖皮质激素调节的蛋白激酶1 （SGK1）是预防和治疗GBM的靶点。Rhein具有抗肿瘤和抑制SGK1的作用，但其生物活性受到生物利用度差的限制。为了提高大黄酸的类药物性质，我们将大黄酸与HDAC抑制剂亚eroylanilide羟肟酸（SAHA）结合，构建了一种新型的大黄酸-羟乙基羟肟酸衍生物（SYSUP007）。本研究以人GBM细胞株T98G、U87和U251为实验对象，研究SYSUP007的体外抗癌作用。我们发现SYSUP007在体外抑制胶质瘤细胞增殖、侵袭和迁移的作用比rhein和SAHA更有效。我们还证实SYSUP007增加了Ac-K100和NDRG1 （HDAC和SGK1的靶点）的表达。本研究表明，SYSUP007作为一种新的大黄酸和SAHA衍生物，具有开发抗癌药物的潜力。
Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system (CNS). Effective treatments remain limited. Therefore, novel chemotherapy drugs with high efficiency and few adverse effects are urgently needed. Histone deacetylase (HDAC) and serum and glucocorticoid-regulated protein kinase 1 (SGK1) are targets for the prevention and treatment of GBM. Rhein has antitumor and SGK1 suppression effects, although its biological activity is limited by poor bioavailability. To improve the drug-like properties of rhein, we constructed a novel rhein-hydroxyethyl hydroxamic acid derivative (SYSUP007), which combined rhein with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA). In the present study, the human GBM cell lines, T98G, U87 and U251, were used to investigate the anticancer effects of SYSUP007 in vitro. We found that SYSUP007 was more effective in inhibiting glioma cell proliferation, invasion and migration in vitro compared with the effects of rhein and SAHA. We also confirmed that SYSUP007 increased the expression of Ac-K100 and NDRG1 (targets of HDAC and SGK1). The present study indicates the potential that SYSUP007, as a novel rhein and SAHA derivative, for development as an anti-cancer therapy.