海洋药物HPN联合替莫唑胺的抗胶质瘤作用及其机制研究

发布时间：2018-03-17 09:23

本文选题：海洋药物HPN　切入点：替莫唑胺　出处：《青岛大学》2017年硕士论文　论文类型：学位论文

【摘要】：神经胶质瘤是最常见的中枢神经系统恶性肿瘤,化学治疗是其重要的辅助治疗手段,目前应用最多的化疗药物是烷化类药物,如替莫唑胺(TMZ)。由于传统化疗药物缺乏针对性、毒副作用大等不足,胶质瘤分子靶向治疗的研究逐渐成为热点。但实践发现,单一应用分子靶向药物往往疗效不明显。在研发出更好的靶向药物之前,靶向药物与传统的化疗药物联合应用表现出了良好的前景。本实验室以海洋植物松节藻的一种提取物为先导物,经结构修饰得到了一种衍生物——3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol(HPN)。体外细胞实验发现,HPN在人神经胶质瘤U87细胞系表现出了良好的抗肿瘤活性,其IC50为6.7μmol/L。在前期体外酶学实验中证实,HPN对蛋白酪氨酸磷酸酶1B(PTP1B)有很好的抑制活性,其IC50达到0.63μmol/L,而且HPN对PTP1B表现出了良好的靶向针对性。本实验研究了海洋药物HPN联合替莫唑胺的抗胶质瘤作用及其机制。MTT结果显示,小剂量HPN与TMZ联合应用,能明显增强TMZ的抗胶质瘤活性。细胞划痕及Transwell小室实验显示,HPN联合TMZ可明显抑制U87细胞迁移、侵袭。Annexin V/PI双染及western blot发现,HPN联合TMZ可促进U87细胞的凋亡。进一步研究发现,HPN可使U87细胞的p-src、p-fak、p-stat3、p-akt、p-erk表达水平下调。通过临床获取的胶质瘤组织及瘤旁组织样本,我们发现胶质瘤组织中PTP1B的表达相对于瘤旁组织明显上调。因此,我们推测HPN可能通过靶向抑制PTP1B进而下调p-src、p-fak、p-stat3、p-akt、p-erk的表达,发挥抗胶质瘤的作用。PTP1B有可能成为胶质瘤分子靶向治疗的新靶点。
[Abstract]:Glioma is the most common malignant tumor of the central nervous system. Chemotherapy is an important adjuvant therapy. At present, alkylation drugs such as temozolamide TMZ are the most commonly used chemotherapeutic drugs, due to the lack of pertinence of traditional chemotherapeutic drugs. The research on molecular targeting therapy of glioma has gradually become a hot topic. However, it has been found in practice that the single application of molecular targeted drugs is often not effective. Before the development of better targeted drugs, The combination of targeted drugs and traditional chemotherapeutic drugs shows good prospects. After structural modification, a derivative, -3O4-Dibromo-5-O2-bromo-3-dihydroxy-6-isopropoxymethyl-benzyl-benzene-1 (2-diolanine) HPNN, was obtained. It was found that HPN exhibited good antitumor activity in human glioma cell line U87 in vitro. Its IC50 was 6.7 渭 mol / L. It was proved that HPN had a good inhibitory activity on protein tyrosine phosphatase 1B (PTP1B) in vitro. Its IC50 reached 0.63 渭 mol / L, and HPN showed a good targeting to PTP1B. In this study, the anti-glioma effect of the marine drug HPN combined with temozolidomide and its mechanism were studied. The cell scratch and Transwell chamber experiments showed that HPN combined with TMZ could significantly inhibit the migration of U87 cells. Invasion. Annexin V / Pi double staining and western blot found that HPN combined with TMZ could promote the apoptosis of U87 cells. Further study showed that HPN could down-regulate the expression of p-srctpp-stat3p-aktna-p-erk in U87 cells. The clinical samples of glioma tissues and adjacent tissues were obtained. We found that the expression of PTP1B was significantly up-regulated in glioma tissues as compared with the adjacent tissues. Therefore, we speculated that HPN might down-regulate the expression of p-srccta-p-fakaka-p-stat3paktna-p-erk by targeting the inhibition of PTP1B. PTP1B may be a new target for glioma molecular targeting therapy.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R739.4

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