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。
1.1 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。
2.1 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]。
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。
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)。
[1] Yonggang Tan, Yiming Meng, Zuozhou Wang, et al. Maturation of morphology, phenotype and functions of murine bone marrowderived dendritic cells(DCs) induced by polysaccharide Kureha(PSK). Hum Vaccin Immunother,2012,8(12):1808.
[2] Tanaka H, Yamazoe S, Iwauchi T, et al. Impacts of PSK and TbetaR inhibitor on immune response in immunosuppressive status associated with cancer. Gan To Kagaku Ryoho,2009,36(12):1969-71.
[3] Hailing Lu, Yi Yang, Ekram Gad,et al. TLR2 agonist PSK activates human NK cells and enhances the anti-tumor effect of HER2-targeted monoclonal antibody therapy.Clin Cancer Res,2011,17(21):6742-6753.
[4] Tsujitani S, Ozaki T, Saito H,et al.The NKG2D expression on CD8+T cells and efficacy ofpolysaccharide K (PSK) in gastric cancer.J Clin Oncol,2008(26):148s.
[5] Hirobumi Asai, Hiroko Iijima, Kenichi Matsunaga, et al. Proteinbound polysaccharide K augments IL-2 production from murine mesenteric lymph node CD4+ T cells by modulating T cell receptor signaling.Cancer Immunol Immunother,2008,57(11):1647-1655.
[6] Hailing Lu, Yi Yang, Ekram Gad, et al. Polysaccharide Krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells.Clin Cancer Res,2011,17(1):67-76.
[7] Kanazawa M, Yoshihara K, Abe H, et al. Effects of PSK on T and dendritic cells differentiation in gastric or colorectal cancer patients. Anticancer Res,2005,25(1B):443-449.
[8] Yoshino S, Yoshimura K, Suzuki N, et al. Immunoregulatory effects of PSK on the Th1/Th2 balance and regulatory T-cells in patients with colorectal cancer.Gan To Kagaku Ryoho,2010,37(12):2234-2236.
[9] Taichi Hamanaka, Yuji Sakasegawa, Akihiro Ohmoto, et al. Anti-prion activity of protein-bound polysaccharide K in prioninfected cellsand animals.Biochemical and Biophysical Research Communications,2011,405(2):285-290.
[10] Shinjiro Maruyama, Taiki Akasaka, Koji Yamada, et al. Protein-bound polysaccharide-K (PSK) directly enhanced IgMproduction in the human B cell line BALL-1.Biomedicine & Pharmacotherapy ,2009,63(6):409-412.
[11] Hirahara N, Edamatsu T, Fujieda A, et al.Protein-bound polysaccharide-K (PSK) induces apoptosis via p38 mitogenactivated protein kinase pathway in promyelomonocytic leukemia HL-60 cells. Anticancer Res,2012,32(7):2631-2637.
[12] Hirahara N, Edamatsu T, Fujieda A, et al. Analysis of the mechanism of apoptosis induction by PSK. Gan To Kagaku Ryoho,2011,38(12):1915-1917.
[13] Umehara S, Fujiwara H, Shiozaki A, et al. PSK induces apoptosis through the inhibition of activated STAT3 in human esophageal carcinoma cells.Internaitonal Journal of Oncology,2012,41(1):61-66.
[14] Yoshihiro Ono,Tetsu Hayashida,Ayano Konagai, et al. Direct inhibition of the transforming growth factor-b pathway by proteinbound polysaccharide through inactivation of Smad2 signaling. Cancer Science,2012,103(2):317-324.
[15] Rosendahl AH, Sun C, Wu D, et al. Polysaccharide-K (PSK) increases p21(WAF/Cip1) and promotes apoptosis in pancreatic cancer cells.Pancreatology,2012,12(6):467-74.
[16] Lisa A, Price, Cynthia A. Wenner, Daniel T. Sloper, et al. Role for toll-like receptor4 in TNF-alpha secretion by murine macrophages in response to polysaccharide Krestin, a Trametes versicolor mushroom extract. Fitoterapia,2010,81(7):914-919.
[17] Koido S, Homma S, Okamoto M, et al. Combined TLR2/4-Activated Dendritic/Tumor Cell Fusions Induce Augmented Cytotoxic T Lymphocytes.PLoS One,2013,8(3):e59280.
[18] Aso K, Goi T, Nakazawa T, et al. The expression of integrins is decreased in colon cancer cells treated with polysaccharide K.Internaitonal Journal of Oncology,2013,42(4):1175-1180.
[19] Hirahara N, Fujioka M, Edamatsu T, et al. Protein-bound polysaccharide-K (PSK) induces apoptosis and inhibits proliferation of promyelomonocytic leukemia HL-60 cells. Anticancer Res,2011,31(9):2733-2738.
[20] Hirahara N, Fujioka M, Fujieda A, et al. Analysis of the mechanism of apoptosis induction by PSK.Gan To Kagaku Ryoho,2010,37(12):2255-2257.
[21] Eva Jiménez-Medina, Enrique Berruguilla, Irene Romero, et al. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis. BMC Cancer,2008,8 (1):78.
[22] Akio Yamasaki, Momoko Shoda, Hiroko Iijima, et al.A Proteinbound Polysaccharide, PSK, Enhances Tumor Suppression Induced by Docetaxel in a Gastric Cancer Xenograft Model.Anticancer Research,2009,29(3):843-850.
[23] Jun Kinoshita, Sachio Fushida, Shinichi Harada, et al. PSK enhances the efficacy of docetaxel in human gastric cancer cells through inhibition of nuclearfactor- κB activation and survivin expression. International Journal of Oncology,2010,36(3):593-600.[24] Cynthia , Mark Martzen, Hailing Lu, et al. Polysaccharide-K augments docetaxel-induced tumor suppressioand antitumor immune response in an immunocompetent murine model of human prostate cancer.International Journal of Oncology,2012,40(4):905-913.
[25] Umehara S, Fujiwara H, Suchi K, et al. PSK-mediated growth suppression and enhancement of5-FU/docetaxel-induced cytotoxicity in human esophageal cancer cell lines. Gan To Kagaku Ryoho,2009,36(12):1972-1974.
[26] Ho J C K, Konerding M A, Gaumann A, et al. Fungal polysaccharopeptide inhibits tumor angiogenesis and tumor groeth in mice. Life Sciences,2004,75(11):1343-1356.
[27] Satoh Y, Goi T, Nakazawa T, et al. Polysaccharide K suppresses angiogenesis in colon cancer cells. Exp Ther Med,2012,4(3):370-374.
[28] Tamagawa K, Horiuchi T, Wada T, et al. Polysaccharide-K (PSK) may suppress surgical stress-induced metastasis in rat colon cancer. Langenbecks Arch Surg,2012,397(3):475-480.
[29] Wada T,Wakamatsu Y,Bannai K,et al. Suppression mechanism of angiogenesis by PSK.Ann Cancer Res Ther,2002(10):93-106.
[30] Anaka H, Muguruma K, Ohira M, et al. Impact of adjuvant immunochemotherapy using protein-bound polysaccharide-K on overall survival of patients with gastric cancer. Anticancer Res,2012,32(8):3427-3433.
[31] Choi JH, Kim YB, Lim HY, et al.5-fluorouracil, mitomycin-C, and polysaccharide-K adjuvant chemoimmunotherapy for locally advanced gastric cancer: the prognostic significance of frequent perineural invasion.Hepatogastroenterology,2007,54(73):290-297.
[32] Tanaka H, Muguruma K, Ohira M, et al. Impact of adjuvant immunochemotherapy using protein-bound polysaccharide-K on overall survival of patients with gastric cancer.Anticancer Res,2012,32(8):3427-3433.
[33] Tanaka H, Muguruma K, Kubo N, et al. Effect of PSK on recurrence of stage II/III gastric cancer.Gan To Kagaku Ryoho,2010,37(12):2258-2260.
[34] Oba K, Teramukai S, Kobayashi M, et al. Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer.Cancer Immunol Immunother,2007,56(6):905-911.
[35] Muguruma K, Tanaka H, Sakurai K, et al. A case of far-advanced gastric cancer successfully treated with S-1/paclitaxel/krestin immunochemotherapy, followed by curative resection. Gan To Kagaku Ryoho,2012,39(12):1770-1772.
[36] Toshimi Sakai,Yuichi Yamashita,Takafumi Maekawa, et al. Immunochemotherapy with PSK and Fluoropyrimidines Improves Long-Term Prognosis for Curatively Resected Colorectal Cancer. Cancer Biotherapy and Radiopharmaceuticals,2008,23(4):461-467.[37] Tomizawa K, Kumamoto T, Hanaoka Y, et al. A retrospective study of UFT and oral leucovorin plus PSK combination adjuvant chemotherapy in patients with stage III colon cancer.Gan To Kagaku Ryoho,2012,39(4):571-575.
[38] Ami K, Nakamura M, Takasaki J, et al. A case of transverse colon cancer without a recurrence lesion after five years from resection of hepatic metastasis. Gan To Kagaku Ryoho,2011,38(12):2298-2300.
[39] Takahashi K, Kakita T, Funayama Y, et al. A case with local recurrence of rectal cancer that responded to S-1 and PSK with long-term complete response. Gan To Kagaku Ryoho,2010,37(11):2199-2201.
[40] Aoyama T, Yoshikawa T, Hayashi T, et al. S-1/krestin immunochemotherapy for patients with advanced gastric cancer.Gan To Kagaku Ryoho,2011,38(12):1921-1923.
[41] Yoshikawa T, Tsuburaya A, Saze Z, et al. Randomized phase II trial to compare S-1 and S-1/PSK for advanced or recurrent gastric cancer-lessons from the results. Gan To Kagaku Ryoho,2011,38(12):1909-1911.
[42] Shibata M, Shimura T, Nishina Y, et al. PSK decreased FOLFOX4-induced peripheral neuropathy and bone marrow suppression in patients with metastatic colorectal cancer.Gan To Kagaku Ryoho,2011,38(5):797-801.
[43] Ohta K, Matsui S, Sato Y,et al. Two cases of long-term survival of metastatic colorectal cancer following treatment withpolysaccharide K and mFOLFOX6 therapy. Gan To Kagaku Ryoho,2012,39(12):1782-1784.
[44] Ryoji Katoh, Mitsuru Ooshiro. Enhancement of Antitumor Effect of Tegafur/Uracil (UFT) plus Leucovorin by Combined Treatment with Protein-Bound Polysaccharide, PSK, in Mouse Models. Cellular & Molecular Immunology,2007,4(4):295-299.
[45] Yoshitani S, Takashima S. Efficacy of postoperative UFT (Tegafur/ Uracil) plus PSK therapies in elderly patients with resected colorectal cancer. Cancer Biother Radiopharm,2009,24(1):35-40.
[46] Ishibashi K, Ishiguro T, Kuwabara K, et al. Administration of polysaccharide K (PSK) for stage III colorectal cancer in clinical practice. Gan To Kagaku Ryoho,2008,35(12):2283-2285.
[47] Susumu Ohwada, Tetsushi Ogawa, Fujio Makita, et al. Beneficial effects of protein-bound polysaccharide K plus tegafur/uracil in patients with stage II or III colorectal cancer: Analysis of immunological parameters. Oncology Reports,2006,15(4):861-868.
110021 中國醫(yī)科大學(xué)附屬盛京醫(yī)院腫瘤科