Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8173, USA.
Stem Cells. 2012 Oct;30(10):2065-75. doi: 10.1002/stem.1139.
Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs appears responsible for tumor initiation and progression and also for resistance to conventional treatment. Here we report that the novel phosphosulindac (OXT-328, PS) selectively and effectively eliminates breast CSCs both in vitro and in vivo. PS reduced cell proliferation and induced apoptosis in various breast CSCs. Breast CSCs are resistant to conventional cancer drugs but are sensitive to PS. Long-term treatment of mixtures of cultured breast CSCs and breast cancer cells with PS preferentially eliminated the CSCs. PS impaired the ability of CSCs to form mammospheres and markedly suppressed the expression of CSC-related genes. More importantly, PS prevented by half (p = .06) the formation of tumors initiated by CSCs in immunodeficient mice, and inhibited by 83% (p < .05) the growth of already formed breast cancer xenografts, reducing the proportion of CSCs in them. PS suppressed the Wnt/β-catenin pathway by stimulating the degradation of β-catenin and its relocalization to the cell membrane and also blocked the epithelial-mesenchymal transition and the generation of breast CSCs. These results indicate that PS has a strong inhibitory effect against breast cancer, acting, at least in part, by targeting CSCs through a signaling mechanism involving Wnt signaling.
针对乳腺癌干细胞（CSC）的药物靶向治疗对于乳腺癌的治疗具有很高的前景，因为一小部分 CSC 似乎负责肿瘤的起始和进展，并且还负责对常规治疗的耐药性。在这里，我们报告了新型磷酸苏林达（OXT-328，PS）在体外和体内选择性且有效地消除乳腺癌 CSC。PS 减少了各种乳腺癌 CSC 的细胞增殖并诱导细胞凋亡。乳腺癌 CSC 对常规癌症药物具有抗性，但对 PS 敏感。用 PS 长期处理培养的乳腺癌 CSC 和乳腺癌细胞混合物可优先消除 CSC。PS 损害了 CSC 形成乳腺球体的能力，并显着抑制了 CSC 相关基因的表达。更重要的是，PS 阻止了一半（p=0.06）由 CSC 引发的肿瘤在免疫缺陷小鼠中的形成，并抑制了已经形成的乳腺癌异种移植物的 83%（p<0.05）生长，减少了其中 CSC 的比例。PS 通过刺激β-catenin 的降解及其重新定位到细胞膜，阻断上皮-间充质转化和乳腺癌 CSC 的产生，从而抑制了 Wnt/β-catenin 通路。这些结果表明 PS 对乳腺癌具有很强的抑制作用，其作用至少部分通过涉及 Wnt 信号的信号机制靶向 CSC。
