陳寧 葉麗紅

·綜述·

芹菜素抑制腫瘤細(xì)胞增殖機(jī)制研究進(jìn)展

陳寧 葉麗紅

本文通過參考近年來對芹菜素抑制腫瘤細(xì)胞增殖作用的研究的相關(guān)文獻(xiàn)，于芹菜素對腫瘤細(xì)胞的增殖抑制作用機(jī)制做了歸納和探討。研究發(fā)現(xiàn)，芹菜素對多種癌細(xì)胞都有抑制其生長和促使其凋亡的作用，其對各種癌細(xì)胞作用的機(jī)理研究已經(jīng)深入到細(xì)胞和分子水平，包括對細(xì)胞凋亡和周期相關(guān)基因的調(diào)控，對細(xì)胞周期G0/G1,S及G2/M期的阻滯，對與凋亡相關(guān)的線粒體途徑和非線粒體途徑的各種酶和蛋白表達(dá)的影響，抑制腫瘤細(xì)胞血管生成以及增強(qiáng)腫瘤細(xì)胞對化療藥物的敏感性等。芹菜素抑制腫瘤細(xì)胞增殖機(jī)理值得我們深入探索，其作為一種自然界廣泛存在的抗癌癥化合物具有廣闊的應(yīng)用前景。

芹菜素； 癌細(xì)胞； 抑制增殖； 機(jī)制

芹菜素(apigenin，API)又稱芹黃素，是一種天然的黃酮類化合物，廣泛存在于自然界中,以植物黃色素的形式在茶葉、蔬菜、水果和香料中廣泛分布，中藥如地錢、西藏雪蓮花、車前子、絡(luò)石藤等中也有很高的含量，近年來通過對芹菜素的研究發(fā)現(xiàn)，芹菜素在抗腫瘤方面作用顯著，對乳腺癌，前列腺癌，膀胱癌，卵巢癌，胃癌，肺癌，胰腺癌等均有一定的抑制作用，現(xiàn)就近年來芹菜素在抑制腫瘤細(xì)胞增殖機(jī)制方面的研究新進(jìn)展作一綜述。

1 調(diào)控凋亡基因

1.1 周期相關(guān)基因

杜俊瑤等[1]用芹菜素處理卵巢癌細(xì)胞CAOV3，發(fā)現(xiàn)存活素(survivin)mRNA的表達(dá)下調(diào)，p21 mRNA的表達(dá)上調(diào)，細(xì)胞周期在G2 /M 期停滯。Zhang等[2]發(fā)現(xiàn)芹菜素作用KYSE-510細(xì)胞后，p21waf1基因上調(diào)表達(dá)，與G2/M期細(xì)胞周期停滯有關(guān)的細(xì)胞周期素(cyclin)B1基因下調(diào)表達(dá)，p21waf1可能通過抑制細(xì)胞周期蛋白依賴性激酶[3](cyclin-dependent kinase ，CDK)1促進(jìn)KYSE-510 細(xì)胞發(fā)生G2/M 期細(xì)胞周期停滯。而芹菜素作用OE33細(xì)胞后，GADD45β、14-3-3σ基因上調(diào)表達(dá), cyclin B1基因下調(diào)表達(dá)，GADD45β能破壞cyclin B/CDK1 結(jié)合狀態(tài)[4]，14-3-3σ則能通過Weel磷酸化CDK1，或使Cdc25c去磷酸化，促進(jìn)cyclin B/CDK1向細(xì)胞核外的轉(zhuǎn)運(yùn)[5]，并控制細(xì)胞進(jìn)入有絲分裂期[6]，從而引起OE33細(xì)胞發(fā)生G2/M期細(xì)胞周期停滯。APC是一種與大腸直腸癌發(fā)生有關(guān)的腫瘤抑制基因，它的功能失調(diào)對于芹菜素誘導(dǎo)細(xì)胞周期停滯有關(guān)鍵作用。Chung C S等[7]發(fā)現(xiàn)在人直腸癌細(xì)胞中，芹菜素使APC的表達(dá)上調(diào)，促使了癌細(xì)胞死亡。

1.2 凋亡相關(guān)基因

在對膀胱癌BIU-87細(xì)胞的研究中，姚善華等[8]研究發(fā)現(xiàn)芹菜素能通過下調(diào)survivin mRNA 和survivin 蛋白表達(dá)，上調(diào)半胱氨酸的天冬氨酸蛋白水解酶(cysteinyl aspartate specific proteinase，Caspase)-3蛋白表達(dá)，明顯抑制細(xì)胞的生長，并促進(jìn)細(xì)胞發(fā)生凋亡。Slusarz A等[9]發(fā)現(xiàn)芹菜素還可通過抑制Gli1 mRNA聚合，阻滯Hedgehog信號轉(zhuǎn)導(dǎo)通路，抑制人前列腺癌細(xì)胞增殖。

1.3 能量攝取、血管形成相關(guān)基因

Melstrom等[10]等發(fā)現(xiàn)芹菜素可通過下調(diào)葡萄糖轉(zhuǎn)運(yùn)蛋白(GLUT-1)mRNA表達(dá)和蛋白質(zhì)的表達(dá)顯著抑制兩種胰腺癌細(xì)胞系CD18和S2-013對葡萄糖的攝取，從而抑制胰腺癌細(xì)胞的生長；還可通過低氧誘導(dǎo)因子1α下調(diào)GLUT-1表達(dá)，以及阻礙血管內(nèi)皮生長因子的表達(dá)，抑制在低氧狀態(tài)下的胰腺癌細(xì)胞CD-18和S2-013的增殖。

2 調(diào)控細(xì)胞周期

2.1 G0/G1期阻滯

Gupta等[11]發(fā)現(xiàn)芹菜素可下調(diào)人前列腺癌細(xì)胞cyclin D1、cyclin D2和cyclin E以及通過p53途徑上調(diào)CDK抑制劑WAF1/p21 and KIP1/p27表達(dá), 從而抑制了CDK2、CDK4、CDK6活性，將細(xì)胞阻滯在G0/ G1期。Shukla S等[12]還發(fā)現(xiàn)經(jīng)芹菜素處理的前列腺癌細(xì)胞和PC-3細(xì)胞中與p38和PI3K-Akt的磷酸化減少相關(guān)的cyclin D1的表達(dá)減少，cyclin D2，E以及結(jié)合的CDK 2, 4和6的明顯抑制，使細(xì)胞阻滯于G0-G1期。

2.2 G1/S期阻滯

Zheng等[13]發(fā)現(xiàn)芹菜素通過P53途徑的p21/WAF1表達(dá)增加使人宮頸癌細(xì)胞G1期阻滯。Bektic等[14]發(fā)現(xiàn)芹菜素可使cyclin D1表達(dá)減少而p21 /WAF1表達(dá)增加來使細(xì)胞發(fā)生G1/S期阻滯。Shukla S等[15]認(rèn)為芹菜素通過使WAF1/p21、KIP1/p27、INK4a/p16 和INK4c/p18的表達(dá)增加，cyclinsD1、D2、E和CDK2、CDK4和CDK6表達(dá)下降，降低Rb在serine780的磷酸化，穩(wěn)定p53 serine15的磷酸化，使芹菜素在前列腺癌移植裸鼠的腫瘤組織中阻滯細(xì)胞周期，從而抑制腫瘤的生長。

2.3 G2/M期阻滯

Kobayashi等[16]發(fā)現(xiàn)芹菜素可以通過P53依賴的途徑誘導(dǎo)P21產(chǎn)生,進(jìn)一步抑制CDK1使細(xì)胞周期阻滯于G2/M期從而發(fā)揮對前列腺癌細(xì)胞的生長抑制作用。Casagrande F等[17]研究發(fā)現(xiàn)芹菜素在黑色素瘤細(xì)胞中可以通過抑制CDK1(cdc2)的Tyr15殘基的磷酸化而抑制CDK1(cdc2)活性,使腫瘤細(xì)胞被阻滯在G2/M期。Wang W等[18]認(rèn)為芹菜素通過抑制cyclin B1結(jié)合的CDK1編碼蛋白激酶的活性，減少cyclin B1及p34(cdc2)激酶的積聚將結(jié)腸癌細(xì)胞SW480，HT-29和Caco-2阻滯在G2/M期。Yin F等[19]則認(rèn)為芹菜素抑制cyclin B1 和 CDK1 蛋白的表達(dá)，導(dǎo)致CDK1激酶活性的抑制，伴有CDK4，cyclin D1和cyclin A蛋白水平的下調(diào)，使MCF-7和MDA-MB-468細(xì)胞被阻滯在G2/M期。Ujiki MB等[20]發(fā)現(xiàn)芹菜素通過下調(diào)cyclin A、cyclin B表達(dá)，以及減少cdc2、cdc25磷酸化誘導(dǎo)胰腺癌細(xì)胞G2/M期阻滯。Choi EJ等[21]用芹菜素處理乳腺癌細(xì)胞SK-BR-3，細(xì)胞周期在G2/M期停滯，CDK1和cyclin A、B含量下降，p53的積累增加，p21水平提高。

3 調(diào)節(jié)參與凋亡的酶和蛋白的表達(dá)

3.1 線粒體途徑

Choi EJ等[21]認(rèn)為芹菜素通過抑制CDK1和積累P53，促進(jìn)下游Bax和細(xì)胞色素C表達(dá)，進(jìn)而增加p21(Cip1)水平，誘導(dǎo)乳腺癌細(xì)胞SK-BR-3凋亡。Gupta等[11]發(fā)現(xiàn)將人激素易感性前列腺癌細(xì)胞加入芹菜素共同培養(yǎng)后，觀察到DNA呈片斷化，Bax/Bcl-2比值增加，細(xì)胞發(fā)生凋亡。I-K1Wang等[22]認(rèn)為芹菜素通過提高細(xì)胞內(nèi)活性氧水平，改變線粒體跨膜電位促使細(xì)胞色素C釋放到胞漿并激活Capase-9的作用，進(jìn)而導(dǎo)致細(xì)胞內(nèi)Caspase-3蛋白酶活化，引起細(xì)胞凋亡。Lu等[23]認(rèn)為芹菜素通過上調(diào)細(xì)胞色素C，AIF和Endo G水平，調(diào)節(jié)Bax/Bcl-2比率，引起Caspase-9和Caspase-3活化，從而引發(fā)人肺癌A549細(xì)胞凋亡，而對于人肺癌H460細(xì)胞，芹菜素通過下調(diào)Bid，Bcl-2，procaspase-8；上調(diào)Bax，caspase-3，AIF，細(xì)胞色素C，GRP78和GADD153的表達(dá)；降低線粒體膜電位以及增加ROS和Ca2+來抑制增殖的[24]。Hussain等[25]研究芹菜素對淋巴瘤細(xì)胞系的影響，發(fā)現(xiàn)淋巴瘤細(xì)胞用芹菜素處理引起p-Bad蛋白去磷酸化，抗凋亡蛋白Bcl-2蛋白和細(xì)胞凋亡蛋白抑制劑(IAPs)下調(diào)，Bax/Bcl2比率增加，同時Bax蛋白構(gòu)象改變，從細(xì)胞質(zhì)移位到線粒體，引起線粒體膜電位下降，隨后細(xì)胞色素C釋放，激活Caspase-9和Caspase-3。

3.2 非線粒體途徑

Tzong-Der Way等[26-27]研究發(fā)現(xiàn)芹菜素能夠誘導(dǎo)HER2/neu過度表達(dá)的乳腺癌細(xì)胞發(fā)生凋亡，是通過減少HER2/neu蛋白的表達(dá)，從而抑制HER2/HER3-PI3K/Akt通路的信號轉(zhuǎn)導(dǎo)，誘導(dǎo)細(xì)胞色素C及Caspase-3的激活而產(chǎn)生的。Lee等[28]認(rèn)為芹菜素通過抑制肝細(xì)胞生長因子(HGF)誘導(dǎo)的AKT磷酸化和PI3K途徑的beta4整合蛋白來抑制MDA-MB-231細(xì)胞增殖。Bektic等[14]發(fā)現(xiàn)芹菜素可使ERK1，ERK2的磷酸化減少，介導(dǎo)MAPK通路抑制前列腺間質(zhì)細(xì)胞的增殖。Shukla S等[15]認(rèn)為芹菜素抑制前列腺癌和PC-3細(xì)胞總RB蛋白和位于Ser780和Ser807/811位點(diǎn)RB蛋白的磷酸化，促進(jìn)ERK1/2和JNK1/2的磷酸化，從而抑制了ELK-1的磷酸化及原癌基因c-fos的表達(dá)，抑制腫瘤細(xì)胞的存活。在其它研究中Shukla S等[29]發(fā)現(xiàn)芹菜素通過對胰島素樣生長因子(IGF)-I誘導(dǎo)的IGF-IR的抑制和對p-Akt的抑制導(dǎo)致GSK-3beta磷酸化和cyclin D1表達(dá)下降，p27/kip1表達(dá)增強(qiáng)，通過IGF/IGF-IR和PI3K/Akt途徑誘導(dǎo)前列腺腫瘤細(xì)胞DU145凋亡。Liang Y C等[30]發(fā)現(xiàn)芹菜素可以通過抑制NF-κB抑制因子激酶活性，減少NF-κB抑制因子降解，下調(diào)NF-κB活性促使腫瘤細(xì)胞凋亡。Seo HS等[31]發(fā)現(xiàn)芹菜素能上調(diào)p53，phospho-p53和p21水平，抑制磷酸化c-Jun氨基端激酶-1(JNK-1)和磷酸化STAT3的表達(dá)和活性，降低胞質(zhì)內(nèi)的κB抑制因子α的磷酸化水平，抑制p65入核，阻斷核因子-κB(NF-κB)通路的活化，誘導(dǎo)HER2過表達(dá)的乳腺癌細(xì)胞MCF-7 vec 和MCF-7 HER2的凋亡。

4 抑制腫瘤血管生成及增強(qiáng)對化療藥物的敏感性

LIU等[32]發(fā)現(xiàn)芹菜素通過抑制人肺癌A549細(xì)胞AKT和p70S6K1活性，致HIF-1和血管內(nèi)皮生長因子表達(dá)下降，從而抑制腫瘤血管生成和細(xì)胞增殖。Choi等[33]發(fā)現(xiàn)芹菜素能下調(diào)Akt和ErbB2的表達(dá)來增加過度表達(dá)ErbB2的乳腺癌MDA-MB-453細(xì)胞對5-氟脲嘧啶的敏感性，促使細(xì)胞凋亡。Kachadourian等[34]報道，在A549細(xì)胞和人類前列腺癌PC-3細(xì)胞中，芹菜素可以顯著降低谷胱甘肽水平，而谷胱甘肽水平的降低可能與細(xì)胞對抗腫瘤藥物的敏感度增強(qiáng)相關(guān)。

5 結(jié)語與展望

芹菜素通過調(diào)控凋亡相關(guān)基因，調(diào)控細(xì)胞周期，調(diào)節(jié)參與細(xì)胞凋亡的蛋白和酶的表達(dá)，化療藥物的增敏等多種途徑抑制腫瘤細(xì)胞增殖，發(fā)揮抗腫瘤作用，并且作為一種天然、低毒、高效的廣泛存在于自然界的天然黃酮類化合物日益受到人們的重視，但是芹菜素具體抑制各種腫瘤細(xì)胞增殖的具體機(jī)理仍未探究清楚，值得深入研究，包括凋亡基因的表達(dá)與蛋白表達(dá)的一致性，芹菜素對其表達(dá)的量效關(guān)系，導(dǎo)致凋亡或周期阻滯的完整信號傳導(dǎo)通路以及通路之間的選擇性及相關(guān)性等?？傊?，芹菜素高效低毒，其抑制腫瘤細(xì)胞增殖的機(jī)制值得繼續(xù)深入探究，并有望據(jù)此研發(fā)新型抗腫瘤藥物。

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(本文編輯：蒲曉田)

Mechanismofapigenin’sinhibitionofcancercellproliferation:ReviewofProgress

CHENNing，YELi-hong.

NanjinguniversityoftraditionalChinesemedicine，Nanjing210046,China

YELi-hong，E-mail:cocolihongye@126.com

In this paper, the mechanism of apigenin’s inhibition of cancer cell proliferation was summarized and discussed with the reference of relevant literatures of inhibition in recent years. The research showed that apigenin had the effects of inhibition of proliferation and cell apotosis induction on various kinds of cancer cells and the mechanism was further concentrated on the cellular and molecular levels such as regulating cell gene related to cell cycle and apotosis，blocking cell cycle of G0/G1,S and G2/M stage，influencing the expression of protein and kidney related to mitochondrial or non-mitochondrial control of apotosis, inhibiting tumor angiogenesis and increasing the sensitivity of tumor cells to chemotherapy drugs. The mechanism of apigenin’s inhibition of cancer cell proliferation is worth our further exploration. Apigenin has broad application prospects as an anticancer compound widely distributed in nature.

Apigenin; Cancer cells; Inhibition of proliferation; Mechanism

科技部“十一五”國家科技支撐計劃( 2006BAI11B08-01)；江蘇省高校優(yōu)勢學(xué)科建設(shè)工程資助項目(PAPD)

210046 ，南京中醫(yī)藥大學(xué)第一臨床醫(yī)學(xué)院[陳寧(碩士研究生)、葉麗紅]

陳寧(1989-)，女，2007級七年制在讀碩士研究生。研究方向：中醫(yī)學(xué)(中西醫(yī)結(jié)合腫瘤內(nèi)科)。E-mail：835569624@qq.com

葉麗紅(1967-)，女，博士，教授，主任醫(yī)師，碩士研究生導(dǎo)師。研究方向：內(nèi)科雜病及腫瘤的中醫(yī)藥防治。E-mail: cocolihongye@126.com

R285.5

A

10.3969/j.issn.1674-1749.2014.02.023

2013-12-06)