漆黃素抗腫瘤作用研究進(jìn)展*

廖洪利，吳　也，臧志和

(1.成都醫(yī)學(xué)院藥學(xué)院，成都　610083；　2.四川海思科制藥有限公司，成都　610041)

漆黃素(fisetin,FIS, 3,3',4',7-四羥基黃酮)，又名非瑟酮，是從漆樹科植物木臘樹(RhussuccedaneaL)等植物中提取的一種天然類黃酮化合物。本品亦存在于蔬菜和水果中，如蘋果、柿子、葡萄、獼猴桃、草莓、洋蔥和黃瓜等[1]。漆黃素具有抗氧化、抗炎等藥理學(xué)特性[2，3]，其分子式為C15H10O6，分子量為286.23。

近年來(lái)，漆黃素在抗腫瘤方面的作用引起了人們的關(guān)注。研究表明，漆黃素可通過(guò)誘導(dǎo)腫瘤細(xì)胞凋亡、影響腫瘤細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)通路、抑制腫瘤細(xì)胞增殖、抑制腫瘤細(xì)胞的遷移和侵襲等途徑發(fā)揮抗腫瘤作用。本文就漆黃素的抗腫瘤作用及其機(jī)制的研究進(jìn)展做簡(jiǎn)要綜述。

1　誘導(dǎo)腫瘤細(xì)胞凋亡

漆黃素主要通過(guò)激活Caspase、下調(diào)BIRC8和Bcl2L2、抑制COX-2等途徑誘導(dǎo)腫瘤細(xì)胞凋亡。

1.1激活Caspase應(yīng)用TRAIL(相關(guān)的凋亡誘導(dǎo)配體)和漆黃素聯(lián)合治療的前列腺癌癥細(xì)胞能夠顯著地活化caspase-8和caspase-3，破壞線粒體膜電位，最終導(dǎo)致癌細(xì)胞凋亡[4]。Ying 等[5]研究提示，漆黃素在人宮頸癌細(xì)胞中通過(guò)caspase-8或caspase-3附屬通道的激活誘導(dǎo)細(xì)胞凋亡。Chen 等[6]研究提示，漆黃素在肝癌細(xì)胞SK-HEP-1中通過(guò)激活caspase 3的級(jí)聯(lián)和替代p21蛋白的表達(dá)誘導(dǎo)細(xì)胞凋亡。Yang 等[7]研究表明，漆黃素以caspase-3缺陷性的人乳腺癌細(xì)胞為靶向，誘導(dǎo)caspase-7相關(guān)的細(xì)胞凋亡以及抑制細(xì)胞自噬。Jang 等[8]發(fā)現(xiàn)，漆黃素能夠在多發(fā)性骨髓瘤U266細(xì)胞中由ROS和AMPK途徑誘導(dǎo)細(xì)胞凋亡，其作用機(jī)制是caspase-3的活化。

1.2下調(diào)BIRC8和Bcl2L2桿狀病毒含IAP重復(fù)序列蛋白baculovirl IAP repeat-containing protein 8(BIRC8)和細(xì)胞凋亡調(diào)節(jié)器Bul-W(Bcl2L2)為高度保守的內(nèi)源性抗細(xì)胞凋亡因子，主要通過(guò)抑制Caspase活性和參與調(diào)解核因子NF-κB的作用而抑制細(xì)胞凋亡。Kim 等[9]通過(guò)實(shí)驗(yàn)證實(shí)，漆黃素在Huh-7細(xì)胞的抗癌作用可能是通過(guò)下調(diào)BIRC8和Bcl2L2而導(dǎo)致的。

1.3抑制COX-2Suh 等[10]的研究表明，漆黃素抑制腫瘤細(xì)胞的COX-2和Wnt / EGFR / NF-κB信號(hào)通路，從而誘導(dǎo)腫瘤細(xì)胞凋亡并抑制結(jié)腸癌的生長(zhǎng)。

2　影響腫瘤細(xì)胞的信號(hào)轉(zhuǎn)導(dǎo)通路

信號(hào)傳導(dǎo)通路是將胞外刺激由細(xì)胞表面?zhèn)魅爰?xì)胞內(nèi)，啟動(dòng)了胞漿中的信號(hào)傳導(dǎo)通路，通過(guò)多種途徑將信號(hào)傳遞到細(xì)胞內(nèi)，促成或抑制特定靶基因的表達(dá)。

2.1影響MAPK信號(hào)通路絲裂原活化蛋白激酶(mitogen activatated protein kinase,MAPK)信號(hào)通路的主要功能是將細(xì)胞外信號(hào)傳導(dǎo)到細(xì)胞及其核內(nèi)，引起細(xì)胞生物學(xué)反應(yīng)。細(xì)胞外調(diào)節(jié)蛋白激酶(extracellularregulatedproteinkinases,ERK)是MAPK信號(hào)通路中的重要成員[11]。Ying 等[5]用漆黃素處理HeLa細(xì)胞時(shí)，發(fā)現(xiàn)漆黃素能持續(xù)激活ERK1/2磷酸化，從而誘導(dǎo)細(xì)胞凋亡，證實(shí)了漆黃素的防癌抗癌作用。

2.2抑制NF-kB通路NF-κB(nuclear factor-κB,NF-κB)是一種核轉(zhuǎn)錄因子，其轉(zhuǎn)錄活性增高與多種癌基因的激活相關(guān)。抑制腫瘤細(xì)胞的NF-κB通路可誘導(dǎo)細(xì)胞凋亡、阻斷細(xì)胞分裂周期，進(jìn)而抑制腫瘤細(xì)胞的增殖[12]。Li 等[13]實(shí)驗(yàn)表明，漆黃素在膀胱癌細(xì)胞的通路中激活p53和抑制NF-κB，從而誘導(dǎo)細(xì)胞周期停滯和細(xì)胞凋亡。

2.3抑制PI3K-Akt 磷脂酰肌醇3激酶(phosphatidylinsoitlo 3-kinase,PI3K)是與細(xì)胞內(nèi)傳導(dǎo)有關(guān)的脂類第二信使，其在腫瘤細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)中起著重要的調(diào)節(jié)作用。Suh 等[14]通過(guò)抑制前列腺癌細(xì)胞中PTEN/PI3K/Akt信號(hào)通路的一個(gè)重要的部分——mTOR信號(hào)通路，誘導(dǎo)自噬性細(xì)胞死亡。Adhami 等[3]評(píng)估了漆黃素對(duì)黑色素瘤、前列腺癌、胰腺癌和肺癌等癌癥的影響，發(fā)現(xiàn)漆黃素作為一種PI3K/Akt和mTOR通路的雙重抑制劑而發(fā)揮抗腫瘤作用。

3　抑制腫瘤細(xì)胞的增殖

腫瘤的發(fā)生發(fā)展與細(xì)胞增殖失控、分化障礙及凋亡受阻緊密相關(guān)。Ravichandran等[15]用漆黃素治療苯并(a)芘誘導(dǎo)肺炎的小鼠，對(duì)其抗增殖療效進(jìn)行評(píng)估，認(rèn)為漆黃素可以用作對(duì)肺癌的化學(xué)預(yù)防制劑。Syed 等[16]研究表明，眼球相關(guān)轉(zhuǎn)錄因子(MITF)-過(guò)度表達(dá)細(xì)胞的流式細(xì)胞分析顯示，漆黃素抑制MITF誘導(dǎo)的細(xì)胞增殖。Kim 等[9]用MTT法評(píng)價(jià)漆黃素對(duì)Huh-7細(xì)胞中的抗增殖效果，數(shù)據(jù)說(shuō)明漆黃素在Huh-7細(xì)胞中是一種有效的抗增殖劑，并且這種效果是由于細(xì)胞凋亡的誘導(dǎo)產(chǎn)生的。

4　抑制腫瘤細(xì)胞的遷移和侵襲

腫瘤細(xì)胞的遷移和侵襲能力對(duì)惡性腫瘤的發(fā)展有極其重要的影響。Liao 等[17]研究發(fā)現(xiàn)，漆黃素能抑制人肺腺癌A549細(xì)胞在體外的遷移和侵襲。Chien 等[18]在非細(xì)胞毒性的濃度的條件下，發(fā)現(xiàn)漆黃素在高轉(zhuǎn)移PC-3細(xì)胞的附著、遷移和侵襲能力中表現(xiàn)出了抑制作用。

5　結(jié)語(yǔ)

綜上所述，天然產(chǎn)物漆黃素可通過(guò)多種途徑抑制腫瘤細(xì)胞的生長(zhǎng)和擴(kuò)散。同時(shí)，漆黃素具有在自然界中分布廣泛、毒副作用小、多途徑發(fā)揮作用等特點(diǎn)，相信隨著對(duì)漆黃素抗腫瘤作用機(jī)制研究的不斷深入，可望使之更科學(xué)合理地應(yīng)用于臨床，為人類健康事業(yè)服務(wù)。

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