Hallett Robin M, Girgis-Gabardo Adele, Gwynne William D, Giacomelli Andrew O, Bisson Jennifer N P, Jensen Jeremy E, Dvorkin-Gheva Anna, Hassell John A
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada.
Oncotarget. 2016 Aug 16;7(33):53137-53152. doi: 10.18632/oncotarget.10614.
Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions.
越来越多的数据表明，人类乳腺肿瘤的发生和发展是由一种罕见的肿瘤细胞亚群驱动的，这种细胞被称为乳腺肿瘤起始细胞（BTIC），它们对放疗和化疗具有抗性。因此，需要消除BTIC活性的疗法来实现乳腺癌患者的持久治愈。为了确定此类疗法，我们使用一种灵敏的检测方法，对包括已批准药物在内的小分子进行了高通量筛选，筛选对象是富含BTIC的小鼠乳腺肿瘤细胞群体。我们发现，血清素再摄取转运体（SERT）和血清素受体的抑制剂，包括用于治疗情绪障碍的已批准药物，通过功能球形成试验以及将经药物处理的肿瘤细胞移植到同基因小鼠体内引发肿瘤形成的实验确定，是小鼠BTIC活性的有效抑制剂。此外，选择性血清素再摄取抑制剂（SSRI）舍曲林（左洛复）与多西他赛（泰索帝）协同作用，可在体内使小鼠乳腺肿瘤缩小。因此，针对血清素能系统的药物可能被重新用于治疗乳腺癌患者，以实现更持久的乳腺癌缓解。
