組蛋白去乙�；�酶抑制劑Vorinostat在神經(jīng)生物學(xué)中的應(yīng)用

Vorinostat (SAHA, MK0683，AbMole，M1780) 是一種廣譜的泛組蛋白去乙�；�酶抑制劑（HDACi）。其化學(xué)結(jié)構(gòu)屬于丁二酰亞胺羥肟酸類化合物，能夠通過直接與HDACs結(jié)合并抑制其活性，增加乙�；�組蛋白的積累，從而調(diào)節(jié)細(xì)胞中的基因表達(dá)，并影響多個(gè)信號(hào)通路。此外，Vorinostat（MK0683）還具有細(xì)胞周期阻滯、凋亡、抑制血管生成等生物活性。研究表明，Vorinostat還可雙向調(diào)控應(yīng)激反應(yīng)基因的表達(dá)（如sod-3、hsp-16.2、skn-1等），Vorinostat在低濃度時(shí)上調(diào)上述基因的表達(dá)，而在高濃度（10μM）時(shí)則呈現(xiàn)抑制或中性效應(yīng)，顯示出劑量依賴性的表觀遺傳調(diào)控特性^[1]。Vorinostat還可通過降低Akt信號(hào)通路的表達(dá)水平，誘導(dǎo)細(xì)胞周期阻滯和程序性死亡^[2]。此外，Vorinostat還可下調(diào)多種表觀遺傳調(diào)控酶（如EZH2、SUV39H1/2、DOT1L等）的表達(dá)，說明其對(duì)表觀遺傳調(diào)控網(wǎng)絡(luò)具有廣泛的影響^[3]。在科研應(yīng)用中，Vorinostat (SAHA)展現(xiàn)出多方面的潛力。首先Vorinostat可抑制多種腫瘤細(xì)胞的增殖，例如結(jié)腸癌細(xì)胞（HCT116、HT29）^[4]、胰腺癌細(xì)胞（AsPC-1）^[5]、肝癌細(xì)胞（LCL-PI 11）^[5]、頭頸部鱗癌（HNSCC）等^[6]。Vorinostat還可用于抑制寄生蟲，其機(jī)制同樣涉及原蟲細(xì)胞中HDAC的抑制^[7]。值得注意的是，組織轉(zhuǎn)谷氨酰胺酶（TG2）的活性狀態(tài)會(huì)影響細(xì)胞對(duì)Vorinostat的敏感性。研究發(fā)現(xiàn)TG2活性的抑制可增強(qiáng)Vorinostat的抗增殖效應(yīng)，而TG2過表達(dá)則導(dǎo)致細(xì)胞耐受性的獲得，提示TG2是Vorinostat耐受機(jī)制中的關(guān)鍵靶點(diǎn)^[8]。在神經(jīng)保護(hù)領(lǐng)域，Vorinostat可逆轉(zhuǎn)β淀粉樣蛋白（Amyloid β Protein）誘導(dǎo)的神經(jīng)損傷，該生物學(xué)活性涉及對(duì)AKT-MDM2-p53通路的調(diào)控^[9]。AbMole為全球科研客戶提供高純度、高生物活性的抑制劑、細(xì)胞因子、人源單抗、天然產(chǎn)物、熒光染料、多肽、靶點(diǎn)蛋白、化合物庫、抗生素等科研試劑，全球大量文獻(xiàn)專利引用。
范例詳解
BMC Cancer. 2016 Nov 7;16(1):857.
科研人員在該文章中探究了Vorinostat對(duì)小細(xì)胞肺癌（SCLC）的抑制作用及聯(lián)合抑制方案的開發(fā)。研究通過體外（H209、H146 細(xì)胞系）和體內(nèi)（H209 異種移植裸鼠）實(shí)驗(yàn)，證實(shí) Vorinostat（HDAC 抑制劑）與順鉑（Cisplatin）聯(lián)合或與Etoposide (VP-16-213) 聯(lián)合使用時(shí)，能比單一處理組更顯著地抑制腫瘤細(xì)胞的活力、并誘導(dǎo)凋亡（激活 caspase-3、促進(jìn) PARP 裂解），以及誘導(dǎo)腫瘤細(xì)胞周期的S期阻滯，同時(shí)提高組蛋白H3和α-微管蛋白的乙�；�水平并持續(xù)抑制胸苷酸合成酶（TS）表達(dá)。本文的核心研究對(duì)象 Vorinostat (SAHA, MK0683，AbMole，M1780) 由AbMole提供。2014年，AbMole的兩款抑制劑分別被西班牙國家心血管研究中心和美國哥倫比亞大學(xué)用于動(dòng)物體內(nèi)實(shí)驗(yàn)，相關(guān)科研成果發(fā)表于頂刊 Nature 和 Nature Medicine。

AbMole是ChemBridge中國區(qū)官方指定合作伙伴。


參考文獻(xiàn)及鳴謝
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