Tubeimoside-I sensitizes temozolomide-resistant glioblastoma cells to chemotherapy by reducing MGMT expression and suppressing EGFR induced PI3K/Akt/mTOR/NF-κB-mediated signaling pathway
Tubeimoside-I sensitizes temozolomide-resistant glioblastoma cells to chemotherapy by reducing MGMT expression and suppressing EGFR induced PI3K/Akt/mTOR/NF-κB-mediated signaling pathway
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DOI：
10.1016/j.phymed.2022.154016
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发表时间：
2022-03-09
期刊：
影响因子：
7.9
通讯作者：
Wang, Qirui
中科院分区：
文献类型：
--
作者：
Tang, Qingfa;Cao, Haihong;Wang, Qirui
背景资料：多形性胶质母细胞瘤（GBM，WHO IV级）是中枢神经系统（CNS）恶性肿瘤之一，发病率高，预后差。使用烷化剂，如替莫唑胺（TMZ），几十年来一直是胶质瘤患者细胞毒性治疗的主要方法。然而，TMZ耐药可能是治疗失败的主要原因之一，到目前为止。在寻找逆转TMZ耐药性的有效药物的过程中，我们发现土贝母皂苷-I（TBMS 1）是一种来自传统中药土贝母（Bolbostemma paniculatum（Maxim.）Franquet等具有逆转GBM对TMZ耐药性的活性。然而，TBMS 1增强GBM化疗敏感性的能力很少被研究，其潜在机制仍不清楚。用途：方法：采用CCK-8法检测TBMS-1和TMZ对人胶质母细胞瘤T98 G和U118 MG细胞的增殖抑制作用。TMZ + TBMS 1处理后，通过EdU试验和克隆形成试验测定细胞增殖。流式细胞仪检测细胞凋亡。DNA损伤和DNA双链断裂（DSB）分别通过切割的聚（ADP-核糖）聚合酶（PARP）、γ H2 AX灶性试验和彗星试验来评估。Western印迹分析检测凋亡相关蛋白和DNA修复酶的表达。结果：TBMS 1对TMZ耐药的T98 G和U118 MG胶质母细胞瘤细胞化疗敏感，并gepia.cancer-pku.cn
Background: Glioblastoma multiforme (GBM, World Health Organization [WHO] grade IV) is one of the malignant Central Nerve System (CNS) tumors with high incidence rate and poor prognosis. The use of alkylating agents, such as temozolomide (TMZ), has been the main method of cytotoxic therapy for glioma patients for decades. However, TMZ resistance may be one of the major reasons for treatment failure, so far. In searching for effective agents to reverse TMZ resistance, we found that Tubeimoside-I (TBMS1), a saponin from traditional Chinese medicine, Bolbostemma paniculatum (Maxim.) Franquet, showed activities of reversing TMZ resistance of GBM. However, the ability of TBMS1 enhancing the chemosensitivity of GBM has been rarely studied, and its underlying mechanisms remain unclear. Purpose: This study purposes to reveal the synergistic effects and mechanism of TBMS1 and TMZ against TMZresistant GBM cells.Methods: CCK8 assay was used to investigate the anti-proliferative effects on grade IV glioblastoma human T98G and U118 MG cells. Cell proliferation was determined by EdU assay and clonogenic assay after TMZ plus TBMS1 treatment. Apoptosis was analyzed by flow cytometry. DNA damage and DNA Double Strand Break (DSB) were assessed by cleaved Poly (ADP-ribose) polymerase (PARP), gamma H2AX Foci Assay and Comet Assay, respectively. Expression of proteins associated with apoptosis and DNA repair enzymes were measured by Western blot analysis. The prognostic significance of key proteins of the epidermal growth factor receptor (EGFR) induced PI3K/Akt/mTOR/NF-Kappa B signaling pathway was analyzed using GEPIA (http://gepia.cancer-pku.cn) and validated by Western blotting.Results: Here we demonstrated that TBMS1 sensitized TMZ-resistant T98G and U118 MG glioblastoma cells to chemotherapy and exhibited promotion of apoptosis and inhibition on cell viability, proliferation and clone