本文選題：海洋藥物HPN　切入點(diǎn)：替莫唑胺　出處：《青島大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：神經(jīng)膠質(zhì)瘤是最常見(jiàn)的中樞神經(jīng)系統(tǒng)惡性腫瘤,化學(xué)治療是其重要的輔助治療手段,目前應(yīng)用最多的化療藥物是烷化類藥物,如替莫唑胺(TMZ)。由于傳統(tǒng)化療藥物缺乏針對(duì)性、毒副作用大等不足,膠質(zhì)瘤分子靶向治療的研究逐漸成為熱點(diǎn)。但實(shí)踐發(fā)現(xiàn),單一應(yīng)用分子靶向藥物往往療效不明顯。在研發(fā)出更好的靶向藥物之前,靶向藥物與傳統(tǒng)的化療藥物聯(lián)合應(yīng)用表現(xiàn)出了良好的前景。本實(shí)驗(yàn)室以海洋植物松節(jié)藻的一種提取物為先導(dǎo)物,經(jīng)結(jié)構(gòu)修飾得到了一種衍生物——3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol(HPN)。體外細(xì)胞實(shí)驗(yàn)發(fā)現(xiàn),HPN在人神經(jīng)膠質(zhì)瘤U87細(xì)胞系表現(xiàn)出了良好的抗腫瘤活性,其IC50為6.7μmol/L。在前期體外酶學(xué)實(shí)驗(yàn)中證實(shí),HPN對(duì)蛋白酪氨酸磷酸酶1B(PTP1B)有很好的抑制活性,其IC50達(dá)到0.63μmol/L,而且HPN對(duì)PTP1B表現(xiàn)出了良好的靶向針對(duì)性。本實(shí)驗(yàn)研究了海洋藥物HPN聯(lián)合替莫唑胺的抗膠質(zhì)瘤作用及其機(jī)制。MTT結(jié)果顯示,小劑量HPN與TMZ聯(lián)合應(yīng)用,能明顯增強(qiáng)TMZ的抗膠質(zhì)瘤活性。細(xì)胞劃痕及Transwell小室實(shí)驗(yàn)顯示,HPN聯(lián)合TMZ可明顯抑制U87細(xì)胞遷移、侵襲。Annexin V/PI雙染及western blot發(fā)現(xiàn),HPN聯(lián)合TMZ可促進(jìn)U87細(xì)胞的凋亡。進(jìn)一步研究發(fā)現(xiàn),HPN可使U87細(xì)胞的p-src、p-fak、p-stat3、p-akt、p-erk表達(dá)水平下調(diào)。通過(guò)臨床獲取的膠質(zhì)瘤組織及瘤旁組織樣本,我們發(fā)現(xiàn)膠質(zhì)瘤組織中PTP1B的表達(dá)相對(duì)于瘤旁組織明顯上調(diào)。因此,我們推測(cè)HPN可能通過(guò)靶向抑制PTP1B進(jìn)而下調(diào)p-src、p-fak、p-stat3、p-akt、p-erk的表達(dá),發(fā)揮抗膠質(zhì)瘤的作用。PTP1B有可能成為膠質(zhì)瘤分子靶向治療的新靶點(diǎn)。
[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.
【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R739.4

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