PSK enhances the efficacy of docetaxel in human gastric cancer cells through inhibition of nuclear factor-κB activation and survivin expression
PSK enhances the efficacy of docetaxel in human gastric cancer cells through inhibition of nuclear factor-κB activation and survivin expression
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DOI：
10.3892/ijo_00000534
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发表时间：
2010-03-01
影响因子：
5.2
通讯作者：
Ohta, Tetsuo
中科院分区：
文献类型：
--
作者：
Kinoshita, Jun;Fushida, Sachio;Ohta, Tetsuo
多西紫杉醇是紫杉烷家族的一员，在进展期胃癌患者中具有抗肿瘤作用。然而，治疗剂量的毒性可能是严重的，导致治疗中断。不良反应引起的剂量减少可能会降低多西紫杉醇的细胞毒作用。PSK是一种蛋白质结合的多糖，在亚洲被用作化学免疫治疗剂已有30多年的历史。在本研究中，我们通过体外和体内的非免疫学作用，研究了PSK对多西他赛对人胃癌细胞毒作用的增强作用。采用体外培养的人胃癌细胞株，用四甲基偶氮唑盐比色法检测PSK对多西紫杉醇的增敏作用。此外，为了阐明其分子机制，我们分析了多西紫杉醇和PSK联合作用下，核因子-kappaB的激活以及随后抗凋亡分子Survivin的产生。因此，采用TMK-1在SCID小鼠体内的移植瘤生长来评价其体内疗效，并用免疫组织化学方法检测移植瘤中Survivin的表达。在体外，PSK增强多西紫杉醇对TMK-1细胞的生长抑制作用。PSK以剂量依赖的方式抑制多西紫杉醇诱导的核因子-kappaB活化。此外，受核因子-kappaB转录调控的Survivin的表达也被PSK抑制。在SCID小鼠中，PSK明显抑制TMK-1皮下移植瘤的生长，并与小剂量多西紫杉醇联合应用，并降低多西紫杉醇诱导的TMK-1皮下移植瘤中Survivin的表达。我们的数据表明，PSK在体外和体内都增强了多西紫杉醇对人胃癌的疗效，至少部分是通过下调小剂量多西紫杉醇诱导的NF-kappa B激活和Survivin表达来实现的。
Docetaxel, a member of the taxane family, induces antitumor effects in patients with advanced gastric cancer. However, toxicity at therapeutic doses can be severe, resulting in discontinuation of therapy. It is possible that dose reduction due to adverse events may decrease the cytotoxic efficacy of docetaxel. PSK, a protein-bound polysaccharide, has been used as a chemoimmunotherapy agent in the treatment of cancer in Asia for over 30 years. In the present study, we investigated the enhancing effects of PSK on the cytotoxicity of docetaxel in human gastric cancer through non-immunological actions both in vitro and in vivo. The sensitization effects of PSK on docetaxel were evaluated by MTT assay using human gastric cancer cell lines in vitro. In addition, to elucidate the molecular mechanism, we analyzed the activation of NF-kappa B and the subsequent production of the antiapoptotic molecule survivin in combined treatment with docetaxel and PSK. Accordingly, TMK-1 xenograft growth in SCID mouse was used to evaluate the in vivo efficacy, and the survivin expression in xenografts was also investigated by immunohistochemistry. In vitro, PSK enhanced docetaxel-induced growth inhibition in TMK-1 cells. The docetaxel-induced NF-kappa B activation was inhibited by adding PSK in a dose-dependent manner. Furthermore, the expression of survivin, which is transcriptionally regulated by NF-kappa B, was also inhibited by treatment with PSK. In SCID mouse, PSK significantly inhibited growth of TMK-1 subcutaneous xenografts in combination with low-dose docetaxel, and decreased the docetaxel-induced survivin expression in TMK-1 xenografts. Our data suggest that PSK enhanced the efficacy of docetaxel against human gastric cancer both in vitro and in vivo, at least in part, by downregulating NF-kappa B activation and survivin expression induced by low-dose docetaxel.