Cui Jihong, Hollmén Maija, Li Lina, Chen Yong, Proulx Steven T, Reker Daniel, Schneider Gisbert, Detmar Michael
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich, Zürich, Switzerland.
Oncotarget. 2017 Jan 3;8(1):1007-1022. doi: 10.18632/oncotarget.13537.
Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24- phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents.
癌症干细胞（CSCs）在癌症的起始、转移、复发及治疗抵抗中发挥着主要作用。靶向癌症干细胞是一种很有前景的癌症治疗策略。本研究的目的是鉴定乳腺癌症干细胞（BCSCs）的选择性抑制剂。我们以细胞活力作为主要终点进行了基于细胞的表型筛选，使用了2546种美国食品药品监督管理局（FDA）批准的药物及类药物分子，作用于源自恶性人乳腺的细胞（HMLER-shEcad细胞，代表BCSCs）和对照永生化非致瘤性人乳腺细胞（HMLE细胞，代表正常干细胞）形成的球体。筛选出了19种化合物。选择了化学相关分子甲磺酸苯扎托品和柠檬酸去托品进行进一步验证，二者均能有效抑制体外BCSCs的球体形成和自我更新。甲磺酸苯扎托品处理减少了具有高醛脱氢酶（ALDH）活性和CD44+/CD24-表型的细胞亚群。在体内，甲磺酸苯扎托品在4T1小鼠模型中抑制肿瘤起始潜能。功能研究表明，甲磺酸苯扎托品通过乙酰胆碱受体、多巴胺转运体/受体和/或组胺受体抑制癌症干细胞的功能。总之，我们的研究结果确定甲磺酸苯扎托品在体外和体内均为BCSCs的抑制剂。本研究还提供了一个用于鉴定其他抗癌症干细胞药物的筛选平台。
