2. Academic Validation
  3. Antiproliferative activities of the second-generation antipsychotic drug sertindole against breast cancers with a potential application for treatment of breast-to-brain metastases

Antiproliferative activities of the second-generation antipsychotic drug sertindole against breast cancers with a potential application for treatment of breast-to-brain metastases

  • Sci Rep. 2018 Oct 25;8(1):15753. doi: 10.1038/s41598-018-33740-0.
Wei Zhang 1 2,  Cunlong Zhang 3,  Feng Liu 1,  Yu Mao 1,  Wei Xu 2,  Tingting Fan 1,  Qinsheng Sun 1 2,  Shengnan He 1,  Yuzong Chen 3,  Wei Guo 4,  Ying Tan 5,  Yuyang Jiang 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, P. R. China.
  • 2 School of Medicine, Tsinghua University, Beijing, 100084, P. R. China.
  • 3 Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518055, P. R. China.
  • 4 School of Medicine, Tsinghua University, Beijing, 100084, P. R. China. weiguo@mail.tsinghua.edu.cn.
  • 5 State Key Laboratory of Chemical Oncogenomics, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, P. R. China. tan.ying@sz.tsinghua.edu.cn.
  • 6 State Key Laboratory of Chemical Oncogenomics, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, P. R. China. jiangyy@sz.tsinghua.edu.cn.
  • 7 Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, P. R. China. jiangyy@sz.tsinghua.edu.cn.
PMID: 30361678 DOI: 10.1038/s41598-018-33740-0
Abstract

Epidemiological observations have shown that schizophrenia patients after long-term drug treatment exhibited reduced tumor incidences. The potential Anticancer effects of antipsychotic drugs are subsequently demonstrated. These drugs are of great interest as agents against untreatable brain metastases because of their ability to traverse the blood-brain barrier (BBB). Most drugs tested thus far are the first-generation antipsychotics (FGAs). But their clinical application may be limited due to high risks of deaths in elderly patients. There is an urgent need to find additional BBB-traversing Anticancer agents with lower risks of deaths. In this work, we investigated antitumor activities of eight second-generation-antipsychotic (SGA) drugs, since they exhibit lower mortality rates than FGAs. We discovered that sertindole showed broad antiproliferative activities against seven Cancer types including 29 cell-lines and exhibited potent effects toward breast Cancer cell-lines, with half maximal concentration to inhibit proliferation by 50% (IC50) as low as 800 nM. We further found that sertindole caused cell death through autophagy-associated Apoptosis and its directly-binding inhibition of 5-HT6 involved in this process. In xenotransplant mice, sertindole administration approaching maximal therapeutic dose attenuated breast-tumor growth by 22.7%. Therefore, our study reveals promising Anticancer potentials of sertindole against breast cancers, with probable applications for breast-to-brain metastases.

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