Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases

被引：3
作者：
Xu, Fuyan [1 ,2 ,3 ]
Xia, Yong [1 ,2 ,3 ,4 ]
Feng, Zhanzhan [1 ,2 ,3 ]
Lin, Wentao [5 ]
Xue, Qiang [1 ,2 ,3 ]
Jiang, Jinrui [6 ]
Yu, Xi [7 ]
Peng, Cuiting [1 ,2 ,3 ]
Luo, Min [8 ]
Yang, Yufei [1 ,2 ,3 ]
Wei, Yuquan [1 ,2 ,3 ]
Yu, Luoting [1 ,2 ,3 ]
机构：
[1] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Dept Rehabil Med, 17 3rd Sect,Ren Min South Rd, Chengdu 610041, Sichuan, Peoples R China
[2] Sichuan Univ, West China Hosp, Canc Ctr, 17 3rd Sect,Ren Min South Rd, Chengdu 610041, Sichuan, Peoples R China
[3] Collaborat Innovat Ctr Biotherapy, 17 3rd Sect,Ren Min South Rd, Chengdu 610041, Sichuan, Peoples R China
[4] Sichuan Univ, Key Lab Rehabil Med, West China Hosp, Chengdu 610041, Sichuan, Peoples R China
[5] Chongqing Med Univ, Affiliated Hosp 1, Dept Plast Surg, Chongqing 400016, Peoples R China
[6] Sichuan Univ, West China Sch Pharm, Chengdu 610041, Sichuan, Peoples R China
[7] Johns Hopkins Univ, Carey Bussiness Sch, Baltimore, MD 21202 USA
[8] Sichuan Univ, West China Hosp Stomatol, Natl Clin Res Ctr Oral Dis, State Key Lab Oral Dis, Chengdu, Sichuan, Peoples R China
来源：
AMERICAN JOURNAL OF CANCER RESEARCH | 2019年 / 9卷 / 03期
基金：
中国博士后科学基金; 中国国家自然科学基金;
关键词：
Fluphenazine; triple negative breast cancer (TNBC); brain metastasis; cell cycle arrest; apoptosis; CELL-CYCLE; THERAPEUTIC TARGETS; IN-VITRO; APOPTOSIS; ARREST; PHARMACOKINETICS; PROGRESSION; INHIBITOR; OUTCOMES; KINASES;
D O I：
暂无
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Triple negative breast cancer (TNBC) patients have a high risk of brain metastases. This deadly disease represents a major challenge for successful treatment, in part because of the poor ability of drugs to penetrate the blood-brain barrier. Antipsychotic drugs show good bioavailability in the brain, and some of them have exhibited anticancer effects in several cancer types. In this study, we investigated the potential of repurposing fluphenazine hydrochloride (Flu) for the treatment of TNBC and the brain metastases. Our data showed that Flu inhibited survival of metastatic TNBC cells. It induced G0/G1 cell cycle arrest and promoted mitochondria-mediated intrinsic apoptosis in vitro. Pharmacokinetic studies in BALB/c mice showed a brain/plasma drug concentration ratio of Flu above 25 for at least 24 hours after dosing. Flu moderately suppressed tumor growth in a TNBC subcutaneous xenograft mouse model. Importantly, Flu exhibited good anti metastatic potential in a mouse brain metastasis model with an inhibition rate of 85%. In addition, Flu showed a strong inhibitory effect on spontaneous lung metastasis. Moreover, Flu didn't cause serious side effects in the mice. Taken together, this study prompts further preclinical and clinical investigation into repurposing Flu for treating metastatic TNBC patients, which urgently need new treatment options.
引用
收藏
页码：459 / +
页数：23
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