Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Int J Oncol. 2011 Oct;39(4):891-8. doi: 10.3892/ijo.2011.1085. Epub 2011 Jun 16.
Triple negative breast cancer (TNBC) has increased recurrence and poor survival, despite a high response rate to neoadjuvant chemotherapy. The aim of this study was to determine whether current drug treatment(s) eliminates bulk of tumor cells, but it has a minimal effect on cancer stem cells (CSCs) leading to tumor recurrence. We studied the effects of PARP inhibitors (AZD2281 and BSI-201), paclitaxel, docetaxel, cisplatin and cisplatin plus TRAIL on CSCs derived from CRL-2335 and MDA-MB-468 TNBC cells in vitro. The in vitro data indicate that cisplatin plus TRIAL treatment was most effective in eliminating CSCs compared to PARP inhibitors, cisplatin, paclitaxel and docetaxel. Treatment with cisplatin plus TRAIL also inhibits Wnt-1 signaling and its downstream target, β-catenin, phospho β-catenin, cyclin D1, increased apoptosis, reduced proliferation and mammosphere formation. Inhibition of Wnt-1 by siRNA significantly reduced the ability of CSCs to form mammospheres compared to control. However, maximum effect was seen in cisplatin plus TRAIL-treated cells. Taken together the data suggest that cisplatin plus TRAIL treatment has the potential of providing a new strategy for improving the therapeutic outcome in TNBC patients.
三阴性乳腺癌（TNBC）尽管对新辅助化疗有较高的反应率，但复发和生存预后仍较差。本研究旨在确定当前的药物治疗是否能消除大量肿瘤细胞，但对导致肿瘤复发的癌症干细胞（CSC）影响甚微。我们研究了 PARP 抑制剂（AZD2281 和 BSI-201）、紫杉醇、多西他赛、顺铂和顺铂联合 TRAIL 对源自 CRL-2335 和 MDA-MB-468 TNBC 细胞的 CSCs 的影响。体外数据表明，与 PARP 抑制剂、顺铂、紫杉醇和多西他赛相比，顺铂联合 TRAIL 治疗对 CSCs 的消除作用最有效。顺铂联合 TRAIL 治疗还抑制了 Wnt-1 信号及其下游靶标β-连环蛋白、磷酸化β-连环蛋白、细胞周期蛋白 D1，增加了细胞凋亡，降低了增殖和乳腺球体形成。与对照相比，用 siRNA 抑制 Wnt-1 显著降低了 CSCs 形成乳腺球体的能力。总之，这些数据表明，顺铂联合 TRAIL 治疗有可能为改善 TNBC 患者的治疗效果提供新策略。
