云芝多糖的抗腫瘤作用研究進(jìn)展

梁語絲 鄒華偉 譚永剛

云芝多糖的抗腫瘤作用研究進(jìn)展

梁語絲 鄒華偉 譚永剛

云芝多糖簡稱PSK, 是從擔(dān)子菌亞門雜色云芝菌中提出的多糖, 具有豐富的生物學(xué)功能, 廣泛應(yīng)用于臨床腫瘤治療。本文就目前國內(nèi)外對云芝多糖的抗腫瘤機(jī)制研究及臨床應(yīng)用研究進(jìn)展做一綜述。

1 對腫瘤免疫的影響

1.1 對DC細(xì)胞的影響 DC細(xì)胞是人體最大的抗原呈遞細(xì)胞, 研究發(fā)現(xiàn), 在癌癥患者體內(nèi), DC細(xì)胞的生物學(xué)功能表達(dá)降低。PSK可以促進(jìn)DC細(xì)胞成熟, 使其高表達(dá)MHCII、CD40、CD80、CD86、CD83及腫瘤壞死因子等［1］。PSK還可通過DC細(xì)胞刺激活化的毒性T細(xì)胞產(chǎn)生TNF-β及IL-12, 抑制腫瘤細(xì)胞［2］。

1.2 對NK細(xì)胞的影響 在小鼠的體內(nèi)研究發(fā)現(xiàn), PSK可以提高NK細(xì)胞的生物學(xué)功能, 間接提高免疫系統(tǒng)的功能［3］。Tsujitani S等［4］人在體外培養(yǎng)NK細(xì)胞, 應(yīng)用PSK干預(yù)后NK細(xì)胞活化增強(qiáng), 腫瘤細(xì)胞增殖受到抑制。

1.3 對CD4+及CD8+等T細(xì)胞的影響 白細(xì)胞介素2(IL-2),由活化的CD4+T細(xì)胞產(chǎn)生, 是所有T細(xì)胞亞群的生長因子。Hirobumi Asai等人的研究顯示, PSK通過T細(xì)胞受體, 刺激活化的CD4+T細(xì)胞產(chǎn)生IL-2［5］, 促進(jìn)T細(xì)胞生長繁殖, 調(diào)控免疫系統(tǒng)。而Hailing Lu等［6］人建立TLR-2基因敲除小鼠乳腺癌模型表明PSK通過CD8+T細(xì)胞及NK細(xì)胞發(fā)揮其功能。

1.4 對Th細(xì)胞的影響 Kanazawa等［7］人研究發(fā)現(xiàn), 在癌癥患者中Th1/Th2比例增大, Th1/Th2比例向Th1傾斜, DC1/ DC2比例向DC1傾斜, 應(yīng)用PSK后, Th1/Th2比例接近正常。PSK還可促進(jìn)大腸癌患者中的Th2細(xì)胞的釋放與激活［8］。

1.5 其他 Taichi Hamanaka等［9］人的研究發(fā)現(xiàn), PSK具有抗朊病毒的能力, 在朊病毒感染的小鼠中證明了其抗朊病毒的能力, 但具體成分及機(jī)制不清。Shinjiro Maruyama等［10］人在體外細(xì)胞實(shí)驗(yàn)證明, PSK 直接作用于B細(xì)胞, 促進(jìn)了B 細(xì)胞分泌IgM, 并且增強(qiáng)了B細(xì)胞原始免疫功能。

2 對腫瘤細(xì)胞的影響

2.1 誘導(dǎo)腫瘤細(xì)胞凋亡 p38MAPK途徑：研究發(fā)現(xiàn)PSK通過促進(jìn)p38MAPK磷酸化, 誘導(dǎo)細(xì)胞凋亡；SB203580是p38MAPK的抑制劑, 同樣可以抑制PSK誘導(dǎo)HL-60細(xì)胞凋亡［11,12］。

SATA途徑：SATA磷酸化后促進(jìn)腫瘤生長分化。研究顯示, PSK作用于SATA3, 抑制其磷酸化, 從而間接誘導(dǎo)腫瘤細(xì)胞凋亡［13］。

TNF途徑：轉(zhuǎn)化因子β(TNF-β)是人體細(xì)胞增殖、分化、轉(zhuǎn)化的重要因子。研究表明, PSK能抑制TNF-β的基因表達(dá), 從而降低TNF-β活性［14］。說明TNF-β是PSK發(fā)揮抑制腫瘤作用的一條路徑。

Toll通路：Toll樣受體(Toll-like receptor, TLR)介導(dǎo)的信號(hào)傳導(dǎo)可導(dǎo)致固有免疫細(xì)胞活化。研究表明, PSK可以通過TLR2及TLR4并協(xié)同p21基因作用使胰腺癌細(xì)胞增殖周期停止, 誘導(dǎo)細(xì)胞凋亡［15］。Hailing Lu等［3］人發(fā)現(xiàn)在將TLR-2基因敲除的小鼠乳腺癌模型中PSK沒有發(fā)揮其抗腫瘤作用, 而TLR基因存在時(shí)PSK能正常發(fā)揮抗腫瘤作用［6］。PSK可通過TLR4刺激巨噬細(xì)胞發(fā)揮作用［16］, 亦可以通過TLR2促進(jìn)CD4表達(dá)增加, 并且促進(jìn)INF的產(chǎn)生, 發(fā)揮其抗腫瘤作用［17］。

其他途徑：Aso K等［18］人研究顯示, PSK直接作用于結(jié)腸癌細(xì)胞, 降低結(jié)腸癌細(xì)胞表面的層粘連蛋白、纖維蛋白原、Ⅳ型膠原及I型膠原等成分, 使其細(xì)胞表面粘附力降低, 誘導(dǎo)癌細(xì)胞凋亡。Caspase可以使細(xì)胞程序性死亡,研究發(fā)現(xiàn)PSK在體外可以通過活化caspase3促進(jìn)HL-60細(xì)胞死亡［19-21］。

2.2 抑制腫瘤細(xì)胞增殖 腫瘤的發(fā)生發(fā)展離不開腫瘤細(xì)胞的增殖。研究顯示PSK與多西他賽有協(xié)同作用, 增強(qiáng)了NF-kB的活性, 抑制了胃癌細(xì)胞的生長［22,23］。在前列腺癌中, PSK結(jié)合多西他賽的抗腫瘤作用要高于單獨(dú)使用多西他賽［24］, 起到了抑制腫瘤細(xì)胞增殖的作用。而Hirahara N等［11］用PSK干擾HL-60細(xì)胞, 細(xì)胞被強(qiáng)抑制［20］。在食管癌細(xì)胞中發(fā)現(xiàn), PSK培養(yǎng)后細(xì)胞癌細(xì)胞活性降低, 增殖減少, 且與5-FU及多西他賽聯(lián)合效果更佳［25］。

2.3 抑制腫瘤血管生成 腫瘤的生長離不開血液, 故抑制腫瘤組織的血管形成是治療腫瘤的另一切入點(diǎn)。研究表明PSK可以降低VEGF, 減少腫瘤組織血管的生成從而發(fā)揮抗腫瘤的作用。J.c.K Ho等［26］的研究中觀察到服用PSK的荷瘤小鼠VEGF的水平明顯降低, 新生血管的活性明顯降低。Satoh Y等［27］研究發(fā)現(xiàn), 新生的結(jié)腸癌細(xì)胞組織有血管生成, 給予PSK后血管生長因子及其基因被抑制。Tamagawa等［28］人發(fā)現(xiàn),小鼠肝臟由于缺血再灌注損傷可以使結(jié)腸癌肝轉(zhuǎn)移, 而應(yīng)用PSK后發(fā)現(xiàn), 在肝轉(zhuǎn)移的癌癥組織中新生血管減少。PSK抑制大鼠模型中的成纖維細(xì)胞生長因子(bFGF)誘導(dǎo)的血管生成, 該機(jī)制可能是由于PSK與成纖維細(xì)胞生長因子直接結(jié)合,抑制成纖維細(xì)胞生長因子誘導(dǎo)的血管內(nèi)皮細(xì)胞增殖［29］。

3 臨床應(yīng)用

對胃癌伴有淋巴結(jié)轉(zhuǎn)移的患者應(yīng)用PSK進(jìn)行輔助化療可提高患者生存率［30,31］。對于N3淋巴結(jié)轉(zhuǎn)移的胃癌患者, 口服化療藥及PSK的患者總體生存率高于單獨(dú)服用化療藥的患者［32］。胃癌患者術(shù)后給予PSK效果較好［33］。對于行胃癌根治術(shù)患者, 術(shù)后給予PSK輔助化療同樣可以提高生存率［34］。Muguruma K等［35］人報(bào)道1例四期胃癌患者, 伴有肝轉(zhuǎn)移及腹腔轉(zhuǎn)移, 應(yīng)用PSK輔助治療后肝轉(zhuǎn)移及腹腔轉(zhuǎn)移灶消失,進(jìn)行了手術(shù)。

在結(jié)直腸癌患者中, Toshimi Sakai等［36］人的臨床研究發(fā)現(xiàn), 結(jié)直腸癌患者應(yīng)用PSK的10年生存率遠(yuǎn)遠(yuǎn)高于對照組, Tomizawa K等［37］人進(jìn)行回顧性研究發(fā)現(xiàn), 對于III期結(jié)腸癌患者口服UFT及亞葉酸鈣加PSK總體生存率提高, Ami K［38］報(bào)道1例結(jié)腸癌肝轉(zhuǎn)移患者, 口服PSK后患者血清CEA下降。1例直腸癌術(shù)后復(fù)發(fā)病例, 給予S-1及PSK口服化療,9周期后腫瘤消失［39］, 說明PSK可以提高S-1抗腫瘤作用,且協(xié)同作用更強(qiáng)［40,41］。FOLFOX4聯(lián)合PSK方案可降低FOLFOX4的副作用發(fā)生率, 間接提高患者生存率［42,43］。在小鼠轉(zhuǎn)移性種植癌模型中, PSK增強(qiáng)了UFT的化療效果［44］,后續(xù)的臨床研究指出, 直腸癌術(shù)后患者給予UFT化療, 聯(lián)合PSK組的患者生存率高于單獨(dú)的UFT化療, 并且耐受較好［45-47］。

PSK在臨床中廣泛應(yīng)用于各個(gè)系統(tǒng)的腫瘤治療以及新輔助放化療, 為臨床工作提供了參考。

4 小結(jié)

云芝多糖的抗腫瘤作用復(fù)雜而強(qiáng)大, 但具體機(jī)制尚未完全清楚, 在抑制調(diào)節(jié)性T細(xì)胞(Treg細(xì)胞)及髓源性抑制細(xì)胞(MDSC)等免疫抑制細(xì)胞方面的應(yīng)用價(jià)值尚不明確。繼續(xù)深入研究其抗腫瘤機(jī)制, 尤其在有效病例中研究探討其主要作用靶點(diǎn), 將為更好地應(yīng)用云芝多糖抗腫瘤治療提供理論依據(jù)。

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