Antipsychotic Zuclopenthixol Inhibits Melanoma Growth and Brain Metastasis by Inducing Apoptosis and Cell Cycle Arrest

作者全名：Lin, Wentao; Xia, Yong; He, Anqi; Chen, Shuang; Zhang, Jie

作者地址：[Lin, Wentao] Chongqing Med Univ, Affiliated Hosp 1, Dept Burn & Plast Surg, Chongqing 400016, Peoples R China; [Xia, Yong; He, Anqi] Sichuan Univ, West China Hosp, Rehabil Med Ctr, Dept Rehabil Med, Chengdu 610041, Sichuan, Peoples R China; [Chen, Shuang] Chongqing Med Univ, Affiliated Hosp 1, Dept Dermatovenereol, Chongqing 400016, Peoples R China; [Zhang, Jie] Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing 400016, Peoples R China

通信作者：Zhang, J (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing 400016, Peoples R China.

来源：FRONTIERS IN BIOSCIENCE-LANDMARK

ESI学科分类：　

WOS号：WOS:001222942200009

JCR分区：Q2

影响因子：3.3

年份：2024

卷号：29

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：zuclopenthixol; cell cycle arrest; brain metastasis; apoptosis; melanoma

摘要：Background: The incidence of melanoma brain metastasis (MBM) is high and significantly compromises patient survival and quality of life. Effective treatment of MBM is made difficult by the blood-brain barrier (BBB), since it restricts the entry of drugs into the brain. Certain anti-psychotic drugs able to cross the BBB have demonstrated efficacy in suppressing brain metastasis in preclinical studies. However, the activity of zuclopenthixol against MBM is not yet clear. Methods: Cell viability assays were employed to investigate the potential of zuclopenthixol in the treatment of MBM. Subsequently, the mechanism of action was investigated by RNA-sequencing (RNAseq), flow cytometry-based cell cycle and apoptosis assays, protein expression analysis, and autophagy flux detection. Additionally, the efficacy of zuclopenthixol against tumor growth was investigated in vivo, including MBM models. Results: Zuclopenthixol inhibited the proliferation of various melanoma cell lines at minimal doses by causing cell cycle arrest in the G0/G1 phase and mitochondrialmediated intrinsic apoptosis. Zuclopenthixol also induced cytoprotective autophagy, and inhibition of autophagy enhanced the antimelanoma effects of zuclopenthixol. Furthermore, zuclopenthixol inhibited the growth of human melanoma tumors in nude mice, as well as the growth of intracranial metastases in a mouse model of MBM. Conclusions: These results demonstrate that zuclopenthixol has significant potential as an effective therapeutic agent for MBM.

基金机构：National Natural Science Foundation of China [81703083]; General Project of Chongqing Natural Science Foundation [cstc20jcyj-msxmx0110]

基金资助正文：This research was funded by the National Natural Science Foundation of China, grant number 81703083; the General Project of Chongqing Natural Science Foundation, grant number cstc20jcyj-msxmx0110.