Li Qi, Ma Zhuang, Liu Yinhua, Kan Xiaoxi, Wang Changjun, Su Bingnan, Li Yuchen, Zhang Yingmei, Wang Pingzhang, Luo Yang, Na Daxiang, Wang Lanlan, Zhang Guoying, Zhu Xiaoxin, Wang Lu
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Department of Immunology, Center for Human Disease Genomics, School of Basic Medical Science, Peking University Health Science Centre, Beijing, China.
FEBS J. 2016 Aug;283(15):2836-52. doi: 10.1111/febs.13767. Epub 2016 Jun 16.
Paclitaxel is the most commonly used chemotherapeutic agent in breast cancer treatment. In addition to its well-known cytotoxic effects, recent studies have shown that paclitaxel has tumor-supportive activities. Importantly, paclitaxel levels are not maintained at the effective concentration through one treatment cycle; rather, the concentration decreases during the cycle as a result of drug metabolism. Therefore, a comprehensive understanding of paclitaxel's effects requires insight into the dose-specific activities of paclitaxel and their influence on cancer cells and the host microenvironment. Here we report that a low dose of paclitaxel enhances metastasis of breast cancer cells to the liver in mouse models. We used microarray analysis to investigate gene expression patterns in invasive breast cancer cells treated with low or clinically relevant high doses of paclitaxel. We also investigated the effects of low doses of paclitaxel on cell migration, invasion and metastasis in vitro and in vivo. The results showed that low doses of paclitaxel promoted inflammation and initiated the epithelial-mesenchymal transition, which enhanced tumor cell migration and invasion in vitro. These effects could be reversed by inhibiting NF-κB. Furthermore, low doses of paclitaxel promoted liver metastasis in mouse xenografts, which correlated with changes in estrogen metabolism in the host liver. Collectively, these findings reveal the paradoxical and dose-dependent effects of paclitaxel on breast cancer cell activity, and suggest that increased consideration be given to potential adverse effects associated with low concentrations of paclitaxel during treatment.
Gene expression microarray data are available in the GEO database under accession number GSE82048.
紫杉醇是乳腺癌治疗中最常用的化疗药物。除了其众所周知的细胞毒性作用外，最近的研究表明紫杉醇具有肿瘤支持活性。重要的是，在一个治疗周期内紫杉醇水平无法维持在有效浓度；相反，由于药物代谢，其浓度在周期内会降低。因此，全面了解紫杉醇的作用需要深入了解紫杉醇的剂量特异性活性及其对癌细胞和宿主微环境的影响。在此我们报告，在小鼠模型中低剂量紫杉醇会增强乳腺癌细胞向肝脏的转移。我们使用微阵列分析来研究用低剂量或临床相关高剂量紫杉醇处理的侵袭性乳腺癌细胞中的基因表达模式。我们还研究了低剂量紫杉醇在体外和体内对细胞迁移、侵袭和转移的影响。结果表明，低剂量紫杉醇促进炎症并引发上皮-间质转化，从而增强体外肿瘤细胞的迁移和侵袭。这些作用可通过抑制NF-κB来逆转。此外，低剂量紫杉醇促进小鼠异种移植瘤中的肝转移，这与宿主肝脏中雌激素代谢的变化相关。总体而言，这些发现揭示了紫杉醇对乳腺癌细胞活性的矛盾且剂量依赖性的影响，并表明在治疗期间应更多地考虑与低浓度紫杉醇相关的潜在不良反应。
基因表达微阵列数据可在GEO数据库中获取，登录号为GSE82048。
