Enhancing Chemosensitivity of Breast Cancer Stem Cells by Downregulating SOX2 and ABCG2 Using Wedelolactone-encapsulated Nanoparticles
Enhancing Chemosensitivity of Breast Cancer Stem Cells by Downregulating SOX2 and ABCG2 Using Wedelolactone-encapsulated Nanoparticles
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DOI：
10.1158/1535-7163.mct-18-0409
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发表时间：
2019-03-01
影响因子：
5.7
通讯作者：
Chatterji, Urmi
中科院分区：
文献类型：
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作者：
Das, Sreemanti;Mukherjee, Pritha;Chatterji, Urmi
乳腺癌治疗的一个主要警告是在局部和远端部位治疗后疾病复发。肿瘤复发归因于化疗耐药癌症干细胞（CSC）的持续存在，需要与常规化疗一起清除。维地内酯是一种天然存在的药物，尽管存在一些局限性，但在不同的癌细胞中显示出抗癌作用，并且对csc大多无效。为了增强其在癌细胞中的生物活性，并进一步靶向CSCs，制备了维德内酯包封的PLGA纳米颗粒（nWdl）。初步结果表明，纳米制剂不仅增加了韦地内酯在乳腺癌细胞和CSC群体中的摄取，还增强了药物在细胞内的保留和缓释。通过下调SOX2和ABCG2来增强药物潴留，这两者都有助于CSCs的耐药。此外，nWdl可阻止上皮细胞向间充质细胞转化，抑制细胞迁移和侵袭，并降低MDA-MB-231细胞中乳腺癌干细胞（BCSC）的百分比。当nWdl与紫杉醇联合使用时（已知紫杉醇对BCSCs无效），nWdl使细胞对紫杉醇的作用敏感，并降低了ALDH刺入BCSCs和乳腺微球的百分比。此外，nWdl还能抑制小鼠实体瘤的生长，并降低CD44(+)/CD24（-/低）的数量。综上所述，我们的数据表明，nWdl降低了BCSCs的转移潜能，通过协调调节多能性和外流基因增强了化学敏感性，从而为有效清除BCSCs的药物递送提供了见解。
A major caveat in the treatment of breast cancer is disease recurrence after therapeutic regime at both local and distal sites. Tumor relapse is attributed to the persistence of chemoresistant cancer stem cells (CSC), which need to be obliterated along with conventional chemotherapy. Wedelolactone, a naturally occurring coumestan, demonstrates anticancer effects in different cancer cells, although with several limitations, and is mostly ineffective against CSCs. To enhance its biological activity in cancer cells and additionally target the CSCs, wedelolactone-encapsulated PLGA nanoparticles (nWdl) were formulated. Initial results indicated that nanoformulation of wedelolactone not only increased its uptake in breast cancer cells and the CSC population, it enhanced drug retention and sustained release within the cells. Enhanced drug retention was achieved by downregulation of SOX2 and ABCG2, both of which contribute to drug resistance of the CSCs. In addition, nWdl prevented epithelial-to-mesenchymal transition, suppressed cell migration and invasion, and reduced the percentage of breast cancer stem cells (BCSC) in MDA-MB-231 cells. When administered in combination with paclitaxel, which is known to be ineffective against BCSCs, nWdl sensitized the cells to the effects of paclitaxel and reduced the percentage of ALDH thorn BCSCs and mammospheres. Furthermore, nWdl suppressed growth of solid tumors in mice and also reduced CD44(+)/CD24(-/low) population. Taken together, our data imply that nWdl decreased metastatic potential of BCSCs, enhanced chemosensitivity through coordinated regulation of pluripotent and efflux genes, and thereby provides an insight into effective drug delivery specifically for obliterating BCSCs.