Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Int J Oncol. 2010 Mar;36(3):593-600. doi: 10.3892/ijo_00000534.
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-kappaB 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-kappaB activation was inhibited by adding PSK in a dose-dependent manner. Furthermore, the expression of survivin, which is transcriptionally regulated by NF-kappaB, 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-kappaB activation and survivin expression induced by low-dose docetaxel.
多西紫杉醇是紫杉烷类家族的一员，可诱导晚期胃癌患者产生抗肿瘤作用。然而，治疗剂量的毒性可能很严重，导致治疗中断。由于不良反应导致的剂量减少可能会降低多西紫杉醇的细胞毒性。PSK 是一种蛋白结合多糖，在亚洲已作为癌症化疗免疫治疗药物使用超过 30 年。本研究通过体外和体内实验，探讨了 PSK 通过非免疫作用增强多西紫杉醇对人胃癌细胞的细胞毒性的作用。通过 MTT 分析法，用体外人胃癌细胞系评估 PSK 对多西紫杉醇的增敏作用。此外，为了阐明分子机制，我们分析了多西紫杉醇和 PSK 联合治疗时 NF-κB 的激活以及随后抗凋亡分子 survivin 的产生。因此，我们使用 TMK-1 异种移植在 SCID 小鼠中评估体内疗效，并通过免疫组化法研究了异种移植中 survivin 的表达。在体外，PSK 增强了 TMK-1 细胞中多西紫杉醇诱导的生长抑制。PSK 以剂量依赖性方式抑制多西紫杉醇诱导的 NF-κB 激活。此外，NF-κB 转录调控的 survivin 表达也被 PSK 处理抑制。在 SCID 小鼠中，PSK 与低剂量多西紫杉醇联合显著抑制 TMK-1 皮下异种移植的生长，并降低 TMK-1 异种移植中多西紫杉醇诱导的 survivin 表达。我们的数据表明，PSK 增强了多西紫杉醇对人胃癌的疗效，至少部分是通过下调低剂量多西紫杉醇诱导的 NF-κB 激活和 survivin 表达。
