辣椒素預(yù)防及抗腫瘤作用機(jī)制研究進(jìn)展

左明， 胡麗貞

610041成都，四川省腫瘤醫(yī)院·研究所，四川省癌癥防治中心，電子科技大學(xué)醫(yī)學(xué)院 臨床營養(yǎng)中心

惡性腫瘤是危害人類健康及生命的重要疾病，已成為我國人群死亡的首要原因[1]。腫瘤的化學(xué)預(yù)防與靶向治療是臨床科研工作者的重點(diǎn)課題，應(yīng)用天然果蔬中的活性化合物進(jìn)行預(yù)防和治療癌癥是目前研究的熱點(diǎn)之一。辣椒是全球廣泛食用的果蔬及香料，在辣椒皮質(zhì)部分存在一種生物堿，即辣椒素(capsaicin)，其具有止痛、抗氧化、抗炎及減肥作用[2]。辣椒素通過靶向激活辣椒素受體(transient receptor potential vanilloid，TRPV)或其他信號通路，對多種腫瘤細(xì)胞，如神經(jīng)膠質(zhì)瘤[3-4]、結(jié)直腸癌[5]、前列腺癌[6]、胃癌[7]、肝癌[8]、膽管癌[9]、非小細(xì)胞肺癌[10]、乳腺癌[11]、纖維肉瘤[12]等產(chǎn)生抗腫瘤活性，還可激發(fā)T細(xì)胞介導(dǎo)的抗腫瘤免疫[13]，進(jìn)而預(yù)防和抗腫瘤生長。本文就辣椒素預(yù)防及抗腫瘤作用機(jī)制相關(guān)研究進(jìn)展進(jìn)行綜述。

1 辣椒素化學(xué)結(jié)構(gòu)圖和基本特性

辣椒素化學(xué)名為反式-8-甲基-N-香草基-6-壬烯酰胺(C18H27NO3)，具有辛辣味、刺激性[14]。天然辣椒素包含辣椒素、二氫辣椒素、去氫辣椒素、高辣椒素、高二氫辣椒素等，辣椒素體內(nèi)代謝有4條途徑[15]：(1)通過氧化形成苯氧基，二聚體化或者與P450 2El 共價結(jié)合失去活性；(2)側(cè)烷基鏈羥基化；(3)辣椒素苯環(huán)去甲基化后，氧化為半苯醌或苯醌類衍生物；(4)辣椒素經(jīng)酰胺水解酶的作用生成香草基胺和脂肪酸。

圖1 辣椒素化學(xué)結(jié)構(gòu)圖

2 辣椒素預(yù)防腫瘤作用

研究發(fā)現(xiàn)辣椒素通過調(diào)控致癌物質(zhì)的代謝，以及致癌物與細(xì)胞DNA之間的相互作用[15-16]，還通過調(diào)節(jié)microRNA表達(dá)，調(diào)控癌癥相關(guān)基因的表達(dá)[17]，阻斷實(shí)驗(yàn)性致癌和致突變過程，發(fā)揮預(yù)防癌癥的作用。

有學(xué)者發(fā)現(xiàn)TRPV1激動劑辣椒素與腸道上皮細(xì)胞表達(dá)的TRPV1相互作用，激活Ca2+/鈣蛋白酶，并導(dǎo)致蛋白酪氨酸磷酸酶1B(PTP1B)的活化來抑制EGFR誘導(dǎo)的上皮細(xì)胞增殖，從而抑制腸腫瘤發(fā)生[18]。在大鼠的喂養(yǎng)實(shí)驗(yàn)中，Kim等[19]發(fā)現(xiàn)，食物中加入辣椒素，能抑制烷化劑誘導(dǎo)的胃腸道腫瘤發(fā)生。在相似的實(shí)驗(yàn)中，Yoshitani等[20]研究表明辣椒素能明顯降低氧化偶氮甲烷誘導(dǎo)的結(jié)腸癌發(fā)生。Anandakumar等[21]研究證明辣椒素對苯并(a)芘誘導(dǎo)的實(shí)驗(yàn)性肺癌有化學(xué)保護(hù)作用。辣椒素還可通過抑制胰腺炎癥和K-ras基因突變，從而預(yù)防胰腺癌[22]。Sirtuin 1是一類依賴于NAD+的組蛋白去乙?；?，近期研究發(fā)現(xiàn)胃癌組織中hMOF(human male absent on the first)蛋白活性降低，而辣椒素可上調(diào)hMOF蛋白的表達(dá)。通過hMOF蛋白介導(dǎo)，辣椒素可作用于癌細(xì)胞中沉默信息調(diào)節(jié)因子 2 ( silent information regulator 2 )相關(guān)酶(Sirtuin 1，SIRT1)，調(diào)節(jié)癌細(xì)胞的組蛋白乙酰化，抑制癌細(xì)胞生長[23]。腫瘤相關(guān)煙酰胺腺嘌呤二核苷酸氧化酶(tumor-associated nicotinamide adenine dinucleotide oxidase，tNOX)位于癌細(xì)胞表面，其對腫瘤細(xì)胞生長至關(guān)重要。在腫瘤臨床癥狀發(fā)生之前幾年，癌癥患者的血清中已存在tNOX，辣椒素作為tNOX的拮抗劑，可抑制tNOX，預(yù)防腫瘤的發(fā)生[24]。還有研究者發(fā)現(xiàn)，辣椒素通過抑制炎癥細(xì)胞因子的產(chǎn)生，調(diào)節(jié)免疫功能，從而預(yù)防結(jié)腸腫瘤[25]。

3 抗腫瘤作用

辣椒素的抗腫瘤作用主要通過辣椒素受體依賴和辣椒素受體非依賴兩條途徑來實(shí)現(xiàn)。大量研究表明，辣椒素通過多種機(jī)制，產(chǎn)生抗腫瘤作用，如引起腫瘤細(xì)胞周期停滯[11,26]、代謝抑制[27-29]、腫瘤壞死[10]、凋亡[3,8,26,30-31]，甚至辣椒素可誘導(dǎo)腫瘤干細(xì)胞(CSC)的凋亡[32]，和自噬[3,33]。凋亡是細(xì)胞主動性程序死亡，主要有死亡受體、線粒體和內(nèi)質(zhì)網(wǎng)途徑；而辣椒素誘導(dǎo)癌細(xì)胞凋亡有兩條始動途徑，通過間接激活TRPV1，或直接激活與上述三條凋亡通路相關(guān)的直接通路[2]，最后激活caspase-3，導(dǎo)致癌細(xì)胞DNA損傷，從而誘導(dǎo)癌細(xì)胞的凋亡[34]。還有研究發(fā)現(xiàn)，辣椒素可以降低腫瘤細(xì)胞的侵襲和轉(zhuǎn)移能力，同時在體內(nèi)外均能抑制腫瘤組織的血管生成[35]。

3.1 辣椒素受體依賴的抗腫瘤機(jī)制

辣椒素激活辣椒素受體產(chǎn)生抗腫瘤作用，主要有誘導(dǎo)腫瘤細(xì)胞凋亡、抗血管生成和降低癌細(xì)胞的轉(zhuǎn)移；其促凋亡途徑有：(1)辣椒素激活TRPV1，誘導(dǎo)凋亡相關(guān)因子FAS / CD95表達(dá)上調(diào)，啟動死亡受體途徑[36-37]。(2)激活p38/ MAPK通路[4]。(3)由TRPV6介導(dǎo)，鈣蛋白酶途徑，導(dǎo)致Ca2+介導(dǎo)的線粒體損傷和細(xì)胞色素c釋放[38]。(4)其他途徑，上調(diào)Fas/ Fas相關(guān)因子1的表達(dá)，誘導(dǎo)癌細(xì)胞凋亡[2]。

辣椒素除依賴?yán)苯匪厥荏w促凋亡外，還有研究發(fā)現(xiàn)辣椒素與TRPV1相互作用，降低尿路上皮癌的侵襲性，減少轉(zhuǎn)移的可能，還可以抗血管生成，從而發(fā)揮抗腫瘤作用[37]。

3.2 辣椒素受體非依賴的抗腫瘤機(jī)制

辣椒素還可通過其他非依賴?yán)苯匪厥荏w的途徑產(chǎn)生抗腫瘤作用。主要有：(1)促進(jìn)癌細(xì)胞凋亡。辣椒素能夠通過線粒體途徑誘導(dǎo)腫瘤細(xì)胞凋亡。Huang等[8]發(fā)現(xiàn)辣椒素顯著降低肝癌細(xì)胞線粒體跨膜電位，增加細(xì)胞內(nèi)Ca2+水平和產(chǎn)生活性氧ROS(reactive oxygen species，ROS)，使細(xì)胞內(nèi)Bax蛋白水平升高，Bcl-2蛋白水平下降，激活caspase-3，而誘導(dǎo)癌細(xì)胞凋亡；或通過線粒體去極化和內(nèi)質(zhì)網(wǎng)應(yīng)激，誘導(dǎo)人鼻咽癌NPC-TW 039細(xì)胞凋亡[31]。辣椒素作為抗氧化劑能夠抑制tNOX，引起細(xì)胞凋亡，發(fā)揮抗腫瘤活性[24]。Shim用不同濃度(5μM，10μM和20μM)的辣椒素處理MCF-7細(xì)胞24小時，腫瘤干細(xì)胞(CSC)數(shù)下降，呈劑量依賴性，用辣椒素(10μM以上)處理時，能夠通過抑制其notch通路，引起乳腺癌CSC凋亡[32]。辣椒素誘導(dǎo)自噬致膠質(zhì)瘤細(xì)胞凋亡[3]。Zheng發(fā)現(xiàn)辣椒素可以通過阻斷PI3K/Akt/mTOR途徑，增加自噬標(biāo)志物L(fēng)C3-II和Atg5的水平，誘導(dǎo)自噬，增強(qiáng)p62和Fap-1降解，增加caspase-3的活性以誘導(dǎo)細(xì)胞凋亡[33]。(2)誘導(dǎo)細(xì)胞周期阻滯，抑制細(xì)胞增殖。結(jié)直腸癌的發(fā)生與β-連環(huán)蛋白(β-catenin)基因遺傳改變相關(guān)，而Lee等[5]發(fā)現(xiàn)辣椒素抑制β-連環(huán)蛋白(β-catenin)的轉(zhuǎn)錄，激活β-catenin蛋白酶體的降解，以及破壞β-catenin/TCF-4的相互作用，發(fā)揮抗結(jié)腸癌細(xì)胞增殖的作用。Chen 等[39]研究表明，辣椒素能夠通過抑制細(xì)胞周期相關(guān)蛋白依賴性激酶(cyclin dependent kinase,CDK))進(jìn)而誘導(dǎo)細(xì)胞周期停滯，從而抑制癌細(xì)胞增殖。Zheng等[40]研究辣椒素對雄激素受體(AR)的調(diào)控，發(fā)現(xiàn)辣椒素通過上調(diào)AR陽性前列腺癌細(xì)胞中miR-449a的表達(dá)，誘導(dǎo)雄激素受體的失活和降解來阻止腫瘤增殖和細(xì)胞周期進(jìn)程。miR-449a的表達(dá)增加可以促進(jìn)前列腺癌對辣椒素治療的敏感性。Brown等[41]研究表明，在四種人小細(xì)胞肺癌(SCLC)細(xì)胞系中顯示出強(qiáng)大的抗增殖活性，并發(fā)現(xiàn)辣椒素的抗增殖活性與細(xì)胞周期蛋白E、胸苷酸合成酶、cdc25A和cdc6在mRNA和蛋白質(zhì)水平上的表達(dá)下降有關(guān)。辣椒素引起E2F4和p130對E2F響應(yīng)性增殖啟動子的募集，誘導(dǎo)G1停滯，E2F信號通路在此過程中發(fā)揮了關(guān)鍵性的作用。

辣椒素抗腫瘤的通路不僅是單一的途徑，而存在多條途徑。Thoennissen等[42]研究發(fā)現(xiàn)辣椒素通過調(diào)節(jié)EGFR /HER-2途徑引起ER陽性和陰性乳腺癌細(xì)胞的細(xì)胞周期阻滯，還可誘導(dǎo)細(xì)胞凋亡，Chang等[26]對乳腺癌細(xì)胞研究也有相似發(fā)現(xiàn)，伴隨線粒體膜電位顯著降低，聚腺苷酸二磷酸核糖轉(zhuǎn)移酶-1[poly(ADP-ribose)polymerase-1，PARP-1]的裂解，半胱天冬酶原-7(procaspase-7)表達(dá)降低，導(dǎo)致細(xì)胞凋亡和細(xì)胞周期發(fā)生S期阻滯。另有學(xué)者在通過對前列腺癌細(xì)胞的研究也有相似的發(fā)現(xiàn)[43]。辣椒素作用于胃癌SNU-1細(xì)胞會產(chǎn)生氧化應(yīng)激，誘導(dǎo)腫瘤相關(guān)NADH氧化酶(tNOX)mRNA轉(zhuǎn)錄和蛋白質(zhì)表達(dá)下調(diào)相關(guān)，導(dǎo)致細(xì)胞凋亡，同時有顯著的細(xì)胞毒性作用，促進(jìn)癌細(xì)胞的壞死[44]。辣椒素是組成型和白介素-6誘導(dǎo)型STAT3激活的阻斷劑，下調(diào)STAT3調(diào)節(jié)基因產(chǎn)物如細(xì)胞周期蛋白D1，Bcl-2，Bcl-xL，生存素(survivin)和血管內(nèi)皮生長因子(VEGF)的表達(dá)，誘導(dǎo)細(xì)胞在G1期停滯和腫瘤細(xì)胞凋亡，還可抗腫瘤血管生成[45]。

辣椒素還可激活p53-SMAR1陽性反饋環(huán)，誘導(dǎo)p53介導(dǎo)的HIF-1α降解，抑制Cox-2的表達(dá)，下調(diào)非小細(xì)胞肺癌(NSCLC)細(xì)胞VEGF的表達(dá)，阻止內(nèi)皮細(xì)胞遷移和血管網(wǎng)形成，改變腫瘤微環(huán)境，導(dǎo)致腫瘤壞死[10]，另有研究表明辣椒素下調(diào)AMPK-NF-kappaB信號通路中MMP-9表達(dá)，抑制膽管癌細(xì)胞的轉(zhuǎn)移[9]。

4 辣椒素與其他抗癌藥物的相互作用

辣椒素與其他抗癌藥物聯(lián)用，具有化學(xué)增敏的效果，能增強(qiáng)抗癌藥物的抗癌活性。辣椒素聯(lián)合5-Fu，抑制胃癌細(xì)胞效果優(yōu)于5-Fu單獨(dú)使用，可能與辣椒素促進(jìn)細(xì)胞色素C的釋放以及抑制IкBα的磷酸化，阻斷NF-kB信號通路有關(guān)[46]。Huh等[47]應(yīng)用辣椒素聯(lián)合順鉑進(jìn)行研究，也有的相似的結(jié)果，發(fā)現(xiàn)辣椒素能提高順鉑的抗癌活性。辣椒素通過激活TRPV1和抑制腫瘤細(xì)胞中PCNA核移位，增強(qiáng)吡柔比星的抗腫瘤增殖效果[48]，還顯著增強(qiáng)硼替佐米(Bortezomib/Velcade)和沙利度胺對多發(fā)性骨髓瘤細(xì)胞中的促凋亡作用[45]。

辣椒素和十字花科蔬菜中生物活性成分二聚吲哚(3,3'-Diindolylmethane，DIM)聯(lián)合應(yīng)用，可通過調(diào)節(jié)NF-kB、p53以及與凋亡相關(guān)靶基因的轉(zhuǎn)錄活性，協(xié)同抑制細(xì)胞增殖并誘導(dǎo)細(xì)胞凋亡[49]。

5 存在的問題及展望

辣椒素具有抗腫瘤作用，可作為癌癥預(yù)防和治療的潛在藥物[7,33,40]，特別是與其他抗癌藥物聯(lián)合應(yīng)用，具有廣泛的應(yīng)用前景[45-49]。辣椒素抗腫瘤作用機(jī)制復(fù)雜，目前具體機(jī)制尚不清楚，還應(yīng)深入研究。但某些情況下辣椒素具有潛在的致癌作用[50]及促腫瘤轉(zhuǎn)移作用[51]，需引起研究者的重視。

雖然動物體內(nèi)研究表明辣椒素能夠顯著抑制癌組織的生長[2]，明顯延長荷瘤小鼠的無進(jìn)展生存期和總生存期[21],近期還有學(xué)者應(yīng)用辣椒素貼劑治療奧沙利鉑化療后誘發(fā)的神經(jīng)病變相關(guān)的疼痛，并取得良好的效果[52]，但目前仍然缺乏辣椒素治療腫瘤的臨床資料。由于辣椒素受體廣泛分布于人體的多種器官和組織，而且具有復(fù)雜的生理和病理功能，在腫瘤治療的同時可能會帶來嚴(yán)重的毒副反應(yīng)[2,53]，此外，辣椒素具有一定刺激性，因此對辣椒素臨床應(yīng)用的安全性還需進(jìn)一步深入研究，降低甚至去除其刺激性，將是未來的研究方向之一。

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