云芝多糖的抗肿瘤作用研究进展

梁语丝 邹华伟 谭永刚

云芝多糖的抗肿瘤作用研究进展

梁语丝 邹华伟 谭永刚

云芝多糖简称PSK, 是从担子菌亚门杂色云芝菌中提出的多糖, 具有丰富的生物学功能, 广泛应用于临床肿瘤治疗。本文就目前国内外对云芝多糖的抗肿瘤机制研究及临床应用研究进展做一综述。

1 对肿瘤免疫的影响

1.1 对DC细胞的影响 DC细胞是人体最大的抗原呈递细胞, 研究发现, 在癌症患者体内, DC细胞的生物学功能表达降低。PSK可以促进DC细胞成熟, 使其高表达MHCII、CD40、CD80、CD86、CD83及肿瘤坏死因子等［1］。PSK还可通过DC细胞刺激活化的毒性T细胞产生TNF-β及IL-12, 抑制肿瘤细胞［2］。

1.2 对NK细胞的影响 在小鼠的体内研究发现, PSK可以提高NK细胞的生物学功能, 间接提高免疫系统的功能［3］。Tsujitani S等［4］人在体外培养NK细胞, 应用PSK干预后NK细胞活化增强, 肿瘤细胞增殖受到抑制。

1.3 对CD4+及CD8+等T细胞的影响 白细胞介素2(IL-2),由活化的CD4+T细胞产生, 是所有T细胞亚群的生长因子。Hirobumi Asai等人的研究显示, PSK通过T细胞受体, 刺激活化的CD4+T细胞产生IL-2［5］, 促进T细胞生长繁殖, 调控免疫系统。而Hailing Lu等［6］人建立TLR-2基因敲除小鼠乳腺癌模型表明PSK通过CD8+T细胞及NK细胞发挥其功能。

1.4 对Th细胞的影响 Kanazawa等［7］人研究发现, 在癌症患者中Th1/Th2比例增大, Th1/Th2比例向Th1倾斜, DC1/ DC2比例向DC1倾斜, 应用PSK后, Th1/Th2比例接近正常。PSK还可促进大肠癌患者中的Th2细胞的释放与激活［8］。

1.5 其他 Taichi Hamanaka等［9］人的研究发现, PSK具有抗朊病毒的能力, 在朊病毒感染的小鼠中证明了其抗朊病毒的能力, 但具体成分及机制不清。Shinjiro Maruyama等［10］人在体外细胞实验证明, PSK 直接作用于B细胞, 促进了B 细胞分泌IgM, 并且增强了B细胞原始免疫功能。

2 对肿瘤细胞的影响

2.1 诱导肿瘤细胞凋亡 p38MAPK途径：研究发现PSK通过促进p38MAPK磷酸化, 诱导细胞凋亡；SB203580是p38MAPK的抑制剂, 同样可以抑制PSK诱导HL-60细胞凋亡［11,12］。

SATA途径：SATA磷酸化后促进肿瘤生长分化。研究显示, PSK作用于SATA3, 抑制其磷酸化, 从而间接诱导肿瘤细胞凋亡［13］。

TNF途径：转化因子β(TNF-β)是人体细胞增殖、分化、转化的重要因子。研究表明, PSK能抑制TNF-β的基因表达, 从而降低TNF-β活性［14］。说明TNF-β是PSK发挥抑制肿瘤作用的一条路径。

Toll通路：Toll样受体(Toll-like receptor, TLR)介导的信号传导可导致固有免疫细胞活化。研究表明, PSK可以通过TLR2及TLR4并协同p21基因作用使胰腺癌细胞增殖周期停止, 诱导细胞凋亡［15］。Hailing Lu等［3］人发现在将TLR-2基因敲除的小鼠乳腺癌模型中PSK没有发挥其抗肿瘤作用, 而TLR基因存在时PSK能正常发挥抗肿瘤作用［6］。PSK可通过TLR4刺激巨噬细胞发挥作用［16］, 亦可以通过TLR2促进CD4表达增加, 并且促进INF的产生, 发挥其抗肿瘤作用［17］。

其他途径：Aso K等［18］人研究显示, PSK直接作用于结肠癌细胞, 降低结肠癌细胞表面的层粘连蛋白、纤维蛋白原、Ⅳ型胶原及I型胶原等成分, 使其细胞表面粘附力降低, 诱导癌细胞凋亡。Caspase可以使细胞程序性死亡,研究发现PSK在体外可以通过活化caspase3促进HL-60细胞死亡［19-21］。

2.2 抑制肿瘤细胞增殖 肿瘤的发生发展离不开肿瘤细胞的增殖。研究显示PSK与多西他赛有协同作用, 增强了NF-kB的活性, 抑制了胃癌细胞的生长［22,23］。在前列腺癌中, PSK结合多西他赛的抗肿瘤作用要高于单独使用多西他赛［24］, 起到了抑制肿瘤细胞增殖的作用。而Hirahara N等［11］用PSK干扰HL-60细胞, 细胞被强抑制［20］。在食管癌细胞中发现, PSK培养后细胞癌细胞活性降低, 增殖减少, 且与5-FU及多西他赛联合效果更佳［25］。

2.3 抑制肿瘤血管生成 肿瘤的生长离不开血液, 故抑制肿瘤组织的血管形成是治疗肿瘤的另一切入点。研究表明PSK可以降低VEGF, 减少肿瘤组织血管的生成从而发挥抗肿瘤的作用。J.c.K Ho等［26］的研究中观察到服用PSK的荷瘤小鼠VEGF的水平明显降低, 新生血管的活性明显降低。Satoh Y等［27］研究发现, 新生的结肠癌细胞组织有血管生成, 给予PSK后血管生长因子及其基因被抑制。Tamagawa等［28］人发现,小鼠肝脏由于缺血再灌注损伤可以使结肠癌肝转移, 而应用PSK后发现, 在肝转移的癌症组织中新生血管减少。PSK抑制大鼠模型中的成纤维细胞生长因子(bFGF)诱导的血管生成, 该机制可能是由于PSK与成纤维细胞生长因子直接结合,抑制成纤维细胞生长因子诱导的血管内皮细胞增殖［29］。

3 临床应用

对胃癌伴有淋巴结转移的患者应用PSK进行辅助化疗可提高患者生存率［30,31］。对于N3淋巴结转移的胃癌患者, 口服化疗药及PSK的患者总体生存率高于单独服用化疗药的患者［32］。胃癌患者术后给予PSK效果较好［33］。对于行胃癌根治术患者, 术后给予PSK辅助化疗同样可以提高生存率［34］。Muguruma K等［35］人报道1例四期胃癌患者, 伴有肝转移及腹腔转移, 应用PSK辅助治疗后肝转移及腹腔转移灶消失,进行了手术。

在结直肠癌患者中, Toshimi Sakai等［36］人的临床研究发现, 结直肠癌患者应用PSK的10年生存率远远高于对照组, Tomizawa K等［37］人进行回顾性研究发现, 对于III期结肠癌患者口服UFT及亚叶酸钙加PSK总体生存率提高, Ami K［38］报道1例结肠癌肝转移患者, 口服PSK后患者血清CEA下降。1例直肠癌术后复发病例, 给予S-1及PSK口服化疗,9周期后肿瘤消失［39］, 说明PSK可以提高S-1抗肿瘤作用,且协同作用更强［40,41］。FOLFOX4联合PSK方案可降低FOLFOX4的副作用发生率, 间接提高患者生存率［42,43］。在小鼠转移性种植癌模型中, PSK增强了UFT的化疗效果［44］,后续的临床研究指出, 直肠癌术后患者给予UFT化疗, 联合PSK组的患者生存率高于单独的UFT化疗, 并且耐受较好［45-47］。

PSK在临床中广泛应用于各个系统的肿瘤治疗以及新辅助放化疗, 为临床工作提供了参考。

4 小结

云芝多糖的抗肿瘤作用复杂而强大, 但具体机制尚未完全清楚, 在抑制调节性T细胞(Treg细胞)及髓源性抑制细胞(MDSC)等免疫抑制细胞方面的应用价值尚不明确。继续深入研究其抗肿瘤机制, 尤其在有效病例中研究探讨其主要作用靶点, 将为更好地应用云芝多糖抗肿瘤治疗提供理论依据。

［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 中国医科大学附属盛京医院肿瘤科