Paclitaxel probably enhances cytotoxicity of natural killer cells against breast carcinoma cells by increasing perforin production
Paclitaxel probably enhances cytotoxicity of natural killer cells against breast carcinoma cells by increasing perforin production
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DOI：
10.1007/s00262-004-0617-6
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发表时间：
2005-05-01
影响因子：
5.8
通讯作者：
Katano, M
中科院分区：
文献类型：
--
作者：
Kubo, M;Morisaki, T;Katano, M
紫杉醇是一种半合成的紫杉烷类化合物，是治疗乳腺癌最有效的化疗药物之一。我们主要关注紫杉醇对自然杀伤（NK）细胞的细胞毒性的影响。用磁珠负选择法从健康志愿者外周血单个核细胞中纯化NK细胞。人乳腺癌细胞系BT-474和NK细胞敏感的红白血病细胞系K562被用作靶标。用标记的靶细胞通过Cr-51释放试验测定NK细胞的细胞毒性。紫杉醇（1 - 100 nM）不影响细胞活力，并以剂量依赖性方式显著增强NK细胞的细胞毒性。尽管紫杉醇不影响NK细胞的Fas-配体表达，但紫杉醇诱导穿孔素（NK细胞介导的细胞毒性中的效应分子）的mRNA和蛋白质产生。康卡霉素A是穿孔素介导的细胞毒性途径的有效抑制剂，可抑制紫杉醇依赖性NK细胞介导的细胞毒性。此外，紫杉醇诱导NK细胞中核因子kappaB（NF-kappaB）的活化。NF-κ B抑制剂吡咯烷二硫代氨基甲酸酯显着抑制紫杉醇诱导的穿孔素表达和NK细胞的细胞毒性。我们的研究结果首次表明，紫杉醇在体外增强人NK细胞的细胞毒性。此外，我们的研究结果表明，增强NK细胞的细胞毒性，增加穿孔素的生产，和NF-κ B激活之间的显着关联。
Paclitaxel, a semisynthetic taxane, is one of the most active chemotherapeutic agents for the treatment of patients with breast cancer. We focused on the effect of paclitaxel on the cytotoxicity of natural killer (NK) cells. NK cells were purified by negative selection with magnetic beads from peripheral blood mononuclear cells of healthy volunteers. A human breast carcinoma cell line BT-474 and an NK cell - sensitive erythroleukemia cell line K562 were used as targets. Cytotoxicity of NK cells was determined by Cr-51-release assay with labeled target cells. Paclitaxel ( 1 - 100 nM) did not affect cellular viability, and significantly enhanced cytotoxicity of NK cells in a dose-dependent manner. Although paclitaxel did not affect Fas-ligand expression of NK cells, paclitaxel induced mRNA and protein production of perforin, an effector molecule in NK cell - mediated cytotoxicity. Concanamycin A, a potent inhibitor of the perforin-mediated cytotoxic pathway, inhibited paclitaxel-dependent NK cell - mediated cytotoxicity. Furthermore, paclitaxel induced activation of nuclear factor kappaB (NF-kappaB) in NK cells. NF-kappaB inhibitor pyrrolidine dithiocarbamate significantly suppressed both paclitaxel-induced perforin expression and NK cell cytotoxicity. Our results show for the first time that paclitaxel enhances in vitro cytotoxicity of human NK cells. Moreover, our results suggest a significant association between enhanced NK cell cytotoxicity, increased perforin production, and NF-kappaB activation.