甘草查爾酮A抗腫瘤作用研究進(jìn)展

劉代婷 徐 巍

(哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院中西醫(yī)結(jié)合科,哈爾濱,150000)

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甘草查爾酮A抗腫瘤作用研究進(jìn)展

劉代婷 徐 巍

(哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院中西醫(yī)結(jié)合科,哈爾濱,150000)

甘草查爾酮A是從甘草根中提取出來(lái)的黃酮類化合物,具有多種藥理學(xué)活性,目前最受關(guān)注的是其抗腫瘤活性,本文將對(duì)近年來(lái)國(guó)內(nèi)外關(guān)于甘草查爾酮A抗腫瘤活性及其機(jī)制的研究進(jìn)展進(jìn)行綜述。

甘草查爾酮A;抗腫瘤活性;細(xì)胞凋亡與增殖

甘草查爾酮A是從甘草根中提取出來(lái)一種黃酮類化合物,目前研究證實(shí)其具有廣泛的藥理學(xué)活性,包括抗腫瘤、抗炎、抗氧化、抗菌、抗寄生蟲及成骨活性、免疫調(diào)節(jié)、解痙攣等多種藥理活性,其中尤以抗腫瘤活性的研究最受關(guān)注[1]。為深入研究甘草查爾酮A的抗腫瘤作用機(jī)制,促進(jìn)其進(jìn)一步開發(fā)和利用,本文將對(duì)現(xiàn)有國(guó)內(nèi)外研究甘草查爾酮A抗腫瘤作用的文獻(xiàn)進(jìn)行綜述。

1 誘導(dǎo)腫瘤細(xì)胞凋亡

細(xì)胞凋亡存在于多細(xì)胞生物的整個(gè)生命過程當(dāng)中,可及時(shí)清除機(jī)體內(nèi)多余和受損傷的細(xì)胞,維持組織器官的穩(wěn)定性[2]。綜合目前文獻(xiàn)報(bào)道,甘草查爾酮A可能通過以下途徑誘導(dǎo)腫瘤細(xì)胞凋亡的發(fā)生。

1.1 激活線粒體凋亡途徑線 線粒體凋亡途徑是細(xì)胞凋亡的主要途徑之一,主要是由于線粒體細(xì)胞色素C通過線粒體PT孔釋放至細(xì)胞質(zhì)中,發(fā)生Caspase級(jí)聯(lián)反應(yīng),從而導(dǎo)致細(xì)胞凋亡。在線粒體凋亡途徑中最為關(guān)鍵的控制因素為Bcl-2家族蛋白,它們主要定位于線粒體外膜,能控制PT孔的開放和閉合,其中促凋亡蛋白Bax、Bid等能促PT孔開放,促進(jìn)線粒體凋亡途徑的活化;而抗凋亡蛋白Bcl-2、Bcl-x等則促PT孔關(guān)閉,抑制線粒體凋亡途徑。最近研究表明甘草查爾酮A對(duì)Bcl-2家族蛋白表達(dá)具有顯著的調(diào)節(jié)作用,能通過調(diào)節(jié)Bcl-2家族蛋白的表達(dá)而誘導(dǎo)細(xì)胞凋亡。多項(xiàng)研究證實(shí)在胃癌、乳腺癌等腫瘤細(xì)胞中,甘草查爾酮A能上調(diào)Bax的表達(dá),使Bcl-2的表達(dá)下調(diào),誘導(dǎo)細(xì)胞凋亡[3-5];Chung等[6]報(bào)道甘草查爾酮A能誘導(dǎo)人卵巢癌OVCAR-3和SK-OV-3細(xì)胞中Bid，Bcl-2，Bcl-xL和survivin等抗凋亡蛋白水平下降,同時(shí)使細(xì)胞線粒體膜膜電位缺失,促進(jìn)細(xì)胞色素C的釋放而激活線粒體凋亡途徑。

甘草查爾酮A除了通過調(diào)控Bcl-2家族蛋白表達(dá)誘導(dǎo)凋亡外,還能通過其他方式激活線粒體凋亡途徑。Yuan X等[7]研究發(fā)現(xiàn)在膀胱癌T24細(xì)胞中,甘草查爾酮A不僅能使線粒體膜電位去極化,線粒體受損而誘導(dǎo)細(xì)胞凋亡,同時(shí)還能使線粒體內(nèi)活性氧(ROS)生成增加,產(chǎn)生氧化應(yīng)激反應(yīng),激活線粒體凋亡途徑,從而誘導(dǎo)細(xì)胞凋亡;Ka Hwi等[8]研究發(fā)現(xiàn)甘草查爾酮A還能通過下調(diào)Sp1蛋白表達(dá),繼而激活線粒體凋亡途徑,導(dǎo)致惡性間皮瘤細(xì)胞的凋亡。

1.2 協(xié)同TRAIL介導(dǎo)的細(xì)胞凋亡途徑 TRAIL是新發(fā)現(xiàn)的TNF超家族成員,它能與死亡受體結(jié)合誘導(dǎo)細(xì)胞凋亡,在死亡受體凋亡途徑中發(fā)揮著重要作用。TRAIL家族中TRAIL-R1和TRAIL-R2主要在腫瘤細(xì)胞表面表達(dá),能激活腫瘤細(xì)胞凋亡途徑,在腫瘤細(xì)胞的凋亡中發(fā)揮著重要的作用。Ewelina等[9]研究證實(shí)前列腺癌細(xì)胞能夠抵抗TRAIL誘導(dǎo)的細(xì)胞凋亡,但將甘草查爾酮A作用于前列腺癌細(xì)胞后,由TRAIL介導(dǎo)的細(xì)胞凋亡顯著增加,說明甘草查爾酮A能加強(qiáng)前列腺癌細(xì)胞對(duì)TRAIL的敏感性,加強(qiáng)TRAIL凋亡通路的活性,促進(jìn)細(xì)胞凋亡;隨后,Ewelina等[10]又在甘草查爾酮A對(duì)宮頸癌細(xì)胞Hela細(xì)胞作用的研究中發(fā)現(xiàn)甘草查爾酮A能使Hela細(xì)胞表面的TRAIL-R1和TRAIL-R2表達(dá)顯著上調(diào),從而促使TRAIL介導(dǎo)的細(xì)胞凋亡增加;Yang等[11]研究發(fā)現(xiàn)甘草查爾酮A能與TRAIL協(xié)同作用,促進(jìn)食管癌細(xì)胞Eca109和TE1的凋亡。Mi-Ra Park等[12]研究證實(shí)甘草查爾酮A通過活化ERK1/2和p38的磷酸化反應(yīng),從而上調(diào)TRAIL的表達(dá),使頭頸部鱗癌細(xì)胞FaDu細(xì)胞的凋亡顯著增加。

1.3 啟動(dòng)內(nèi)質(zhì)網(wǎng)凋亡途徑 內(nèi)質(zhì)網(wǎng)(Endoplasmic Reticulum,ER)是真核細(xì)胞中蛋白質(zhì)翻譯合成和細(xì)胞內(nèi)鈣離子的儲(chǔ)存場(chǎng)所,對(duì)細(xì)胞應(yīng)激反應(yīng)起調(diào)節(jié)作用。近年來(lái)研究發(fā)現(xiàn)一旦發(fā)生過度內(nèi)質(zhì)網(wǎng)應(yīng)激后會(huì)啟動(dòng)細(xì)胞凋亡程序,這條新近發(fā)現(xiàn)的細(xì)胞凋亡通路稱為內(nèi)質(zhì)網(wǎng)凋亡途徑。A-Young等[13]研究發(fā)現(xiàn)甘草查爾酮A能誘導(dǎo)肝癌細(xì)胞HepG2細(xì)胞中內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)蛋白CHOP表達(dá)、PLCγ1發(fā)生磷酸化反應(yīng)以及胞質(zhì)中Ca2+和活性氧(ROS)的堆積而發(fā)生過度的內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng),從而啟動(dòng)內(nèi)質(zhì)網(wǎng)凋亡途徑導(dǎo)致HepG2細(xì)胞凋亡。Yuan X等[7]甘草查爾酮A可能通過上調(diào)GRP78和CHOP的表達(dá)水平、激活Caspase-12而啟動(dòng)內(nèi)質(zhì)網(wǎng)凋亡途徑,誘導(dǎo)膀胱癌T24細(xì)胞凋亡。

1.4 其他促腫瘤細(xì)胞凋亡機(jī)制 除了上述凋亡途徑外,甘草查爾酮A還能對(duì)其他凋亡相關(guān)因子產(chǎn)生影響而誘導(dǎo)腫瘤細(xì)胞的凋亡。Jae-Sung等[14]將甘草查爾酮A作用于人口腔癌KB細(xì)胞后發(fā)現(xiàn)細(xì)胞內(nèi)FasL表達(dá)顯著增加,FasL信號(hào)通路中的下游蛋白Caspase-3和Caspase-8的表達(dá)也相應(yīng)地增加,KB細(xì)胞凋亡率顯著增加;MAPK信號(hào)通路也是參與細(xì)胞凋亡的重要通路,Hao等[15]研究發(fā)現(xiàn)甘草查爾酮A可能通過激活胃癌BGC-823細(xì)胞內(nèi)ERK、JNK、p38蛋白,活化MAPK信號(hào)通路而誘導(dǎo)BGC-823細(xì)胞凋亡。

2 抑制腫瘤細(xì)胞增殖

腫瘤細(xì)胞的主要生物學(xué)特點(diǎn)是能給自己提供充足的生長(zhǎng)信號(hào),具有無(wú)限的增殖能力[16],所以抑制腫瘤細(xì)胞增殖對(duì)于腫瘤的治療具有重要意義。大量研究顯示甘草查爾酮A能抑制多種腫瘤細(xì)胞的增殖,其抑制腫瘤細(xì)胞增殖可能與阻滯腫瘤細(xì)胞周期和調(diào)節(jié)細(xì)胞增殖相關(guān)信號(hào)通路有關(guān)。

2.1 阻滯腫瘤細(xì)胞周期 腫瘤細(xì)胞的惡性增殖與細(xì)胞周期的運(yùn)轉(zhuǎn)之間存在著密切的聯(lián)系,阻遏細(xì)胞周期能有效遏制腫瘤細(xì)胞增殖。細(xì)胞周期的調(diào)節(jié)由多種細(xì)胞內(nèi)外因素控制,其中細(xì)胞周期蛋白家族(cyclin)和周期蛋白依賴激酶家族(Cdk)發(fā)揮著至關(guān)重要作用。Yao等[17]報(bào)道甘草查爾酮A不僅能誘導(dǎo)結(jié)腸癌細(xì)胞HCT116凋亡,還能通過上調(diào)P53和P21蛋白的表達(dá),下調(diào)c-Jun活性而使細(xì)胞周期阻滯在G1期;Fu等[18]發(fā)現(xiàn)甘草查爾酮A能抑制前列腺癌PC-3細(xì)胞中cyclin B1、cdc2、CDKs4、CDKs6表達(dá),使cyclinE的表達(dá)增加,將細(xì)胞周期阻滯在G2/M期;其次甘草查爾酮A還能降低PC-3細(xì)胞中過磷酸化Rb蛋白水平,其與轉(zhuǎn)錄因子E2F結(jié)合后可以促進(jìn)細(xì)胞增殖,過磷酸化Rb蛋白水平下降直接抑制了PC-3細(xì)胞的增殖;Zeng等報(bào)道[19]甘草查爾酮A能將口腔鱗癌細(xì)胞SCC-25細(xì)胞周期阻滯在G2/M期,顯著抑制細(xì)胞增殖。

2.2 下調(diào)PI3K/AKT信號(hào)通路活性 PI3K/AKT信號(hào)通路在細(xì)胞增殖中發(fā)揮著重要的作用。Hao等[15]的研究表明甘草查爾酮A使胃癌細(xì)胞BGC-823中PI3K、AKT活性降低,阻礙PI3K/AKT通路信號(hào)傳導(dǎo),抑制BGC-823細(xì)胞的增殖。

3 抑制腫瘤細(xì)胞轉(zhuǎn)移和侵襲

侵襲與轉(zhuǎn)移是惡性腫瘤的主要生物學(xué)特征,是指原發(fā)部位的腫瘤細(xì)胞脫離原發(fā)病灶,侵襲、轉(zhuǎn)移至周圍組織或遠(yuǎn)處靶器官,持續(xù)增殖而形成轉(zhuǎn)移灶的過程。腫瘤侵襲與轉(zhuǎn)移過程十分復(fù)雜,主要受細(xì)胞外基質(zhì)(ECM)降解、細(xì)胞黏附分子、腫瘤血管形成及腫瘤微環(huán)境等多重因素影響[20]。目前已有體內(nèi)、外實(shí)驗(yàn)證實(shí)甘草查爾酮A能抑制腫瘤細(xì)胞侵襲和轉(zhuǎn)移。Kim等[21]通過小鼠結(jié)腸腺癌CT26細(xì)胞肝轉(zhuǎn)移模型及體外證實(shí),甘草查爾酮A能顯著抑制結(jié)腸腺癌CT26細(xì)胞肝轉(zhuǎn)移。

研究表明基質(zhì)金屬蛋白酶(MMPs)和尿激酶型纖溶酶原激活因子(uPA)等對(duì)細(xì)胞外基質(zhì)均具有廣泛的降解作用,能促進(jìn)細(xì)胞侵襲和轉(zhuǎn)移。NF-κB、Akt等信號(hào)通路能調(diào)節(jié)MMPs、TIMPs、細(xì)胞黏附分子及uPA等蛋白的表達(dá),因而在細(xì)胞的侵襲和轉(zhuǎn)移中起著重要的作用。Shen等[22]研究發(fā)現(xiàn)甘草查爾酮A能抑制口腔癌細(xì)胞SCC-25中NF-κB的活性,使MMP-2、N-鈣黏素水平降低,TIMP-2、E-鈣黏素水平升高,從而抑制SCC-25的侵襲與轉(zhuǎn)移。Tsai等[23]發(fā)現(xiàn)甘草查爾酮A能通過下調(diào)MKK4、JNK蛋白的活性,阻礙MKK4/JNK信號(hào)通路,抑制uPA活性,最終達(dá)到抑制肝癌細(xì)胞SK-Hep-1和HA22T/VGH的遷移和侵襲結(jié)果。Huang等[24]的研究表明甘草查爾酮A可能通過使Akt信號(hào)通路失活,MMP1和MMP3的表達(dá)下調(diào)而抑制肺癌細(xì)胞A549和H460的轉(zhuǎn)移和侵襲。

4 抑制腫瘤血管生成

腫瘤血管可以為腫瘤細(xì)胞提供生長(zhǎng)、侵襲與轉(zhuǎn)移所必需的氧氣、營(yíng)養(yǎng)成分及腫瘤生長(zhǎng)因子等,在腫瘤的發(fā)生、發(fā)展中發(fā)揮著重要作用。VEGFR-2是轉(zhuǎn)導(dǎo)VEGF血管新生信號(hào)的關(guān)鍵受體,含有多個(gè)酪氨酸磷酸化位點(diǎn),參與調(diào)控VEGF通路的細(xì)胞增殖、細(xì)胞存活、遷移和血管形成[25]。Kim等[26]的體內(nèi)、外實(shí)驗(yàn)表明甘草查爾酮A能抑制新生血管生成,可能與其抑制血管生成因子IL-6、IL-8的釋放及VEGFR-2信號(hào)通路有關(guān);Jin-Hee等[27]研究發(fā)現(xiàn)甘草查爾酮A可能通過抑制血小板源性生長(zhǎng)因子(PDGF)介導(dǎo)的ERK1/2信號(hào)通路和Rb蛋白磷酸化過程而抑制血管平滑肌細(xì)胞的增殖。

5 其他抗腫瘤機(jī)制

甘草查爾酮A還能誘導(dǎo)腫瘤細(xì)胞自噬,促進(jìn)腫瘤細(xì)胞死亡。Yo等[28]研究發(fā)現(xiàn)用甘草查爾酮A處理人前列腺癌細(xì)胞LNCaP后,出現(xiàn)一系列細(xì)胞自噬的形態(tài)學(xué)表現(xiàn),與此同時(shí)還發(fā)現(xiàn)甘草查爾酮A能使Bcl-2的表達(dá)下調(diào),對(duì)mTOR信號(hào)通路產(chǎn)生抑制作用;甘草查爾酮A還能與抗腫瘤藥物協(xié)同作用,Kim等[29]發(fā)現(xiàn)甘草查爾酮A還能顯著增強(qiáng)格爾德霉素對(duì)人卵巢癌細(xì)胞的促凋亡作用,可能與其激活Caspase-8/Bid依賴性信號(hào)通路和線粒體凋亡通路有關(guān)。

6 討論

腫瘤細(xì)胞的無(wú)限增殖、侵襲與轉(zhuǎn)移是惡性腫瘤最顯著的生物學(xué)特征之一,腫瘤微環(huán)境又被認(rèn)為是腫瘤增殖、侵襲遷移、黏附、及新生血管形成的重要原因。當(dāng)前研究表明運(yùn)用中醫(yī)藥對(duì)腫瘤微環(huán)境進(jìn)行調(diào)控,抑制腫瘤進(jìn)展與惡化,延長(zhǎng)腫瘤患者生存時(shí)間,提高患者生活質(zhì)量。甘草查爾酮A是從常用中藥甘草中提取出來(lái)的具有多重藥理活性的黃酮類化合物,近年來(lái)研究證實(shí)它能通過調(diào)節(jié)相關(guān)蛋白表達(dá)及信號(hào)通路而誘導(dǎo)腫瘤細(xì)胞凋亡、抑制腫瘤細(xì)胞增殖、抑制腫瘤侵襲和轉(zhuǎn)移以及腫瘤血管的生成等多種機(jī)制而發(fā)揮抗腫瘤作用。腫瘤的發(fā)生發(fā)展是一個(gè)極其復(fù)雜的過程,目前關(guān)于甘草查爾酮A抗腫瘤機(jī)制的研究仍有許多不明確的部分,需要進(jìn)行更多的實(shí)驗(yàn)研究為闡明其抗腫瘤機(jī)制提供實(shí)驗(yàn)依據(jù),為研發(fā)甘草查爾酮A作為高效低毒的抗腫瘤藥物提供進(jìn)一步的理論基礎(chǔ)。

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(2016-01-26收稿 責(zé)任編輯：王明)

Research Progress of Anti-tumor effects of Licochalcone A

Liu Daiting,Xu Wei

(DepartmentofintegratedtraditionalChineseandWesternmedicine，F(xiàn)irstAffiliatedHospitalofHarbinMedicalUniversity，Harbin150000,China)

Licochalcone A(LCA) is a flavonoid extracted from licorice root and has a variety of pharmacological activity.Recently,more attention has been focused on the application of LCA in cancer chemopreventive therapy.This article summarized the antitumor activity of LCA and its mechanism combining with domestic and foreign literatures.

Licochalcone A; Antitumor activity; Cell proliferation and apoptosis

哈爾濱領(lǐng)軍人才科研基金項(xiàng)目(編號(hào):2011RFXYS079)

R273;R285.6

A

10.3969/j.issn.1673-7202.2016.10.069