Fuyan Xu1,2,3, Huizhi Xi2, Mengya Liao4, Yiqian Zhang5, Hongbo Ma5, Mengling Wu2, Qiang Xue1, Hongbao Sun6, Yiwen Zhang7, Yong Xia8,9,10. 1. Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. 2. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. 3. Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu, 610041, China. 4. Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China. 5. West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. 6. Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, China. 773770248@qq.com. 7. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. yiwenzhang@scu.edu.cn. 8. Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China. yxia4@scu.edu.cn. 9. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. yxia4@scu.edu.cn. 10. Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu, 610041, China. yxia4@scu.edu.cn.
Abstract
PURPOSE: Despite efforts in developing effective therapeutic strategies, colorectal cancer (CRC) remains one of the most prevalent and lethal neoplasms. Repurposing approved drugs is an alluring strategy for developing anticancer agents. Some antipsychotic drugs, including chlorpromazine (CPZ), possess anticancer activities. However, the pharmacological effects of CPZ on CRC have not been clearly established. METHODS: MTT assay, flow cytometry, western blotting analysis, subcutaneous mice tumor, and tail-vein-injection established lung metastasis model were used to investigate the anticancer effects of CPZ on CRC and the underlying mechanism. RESULTS: We found that CPZ effectively suppressed CRC by inducing G2/M cell cycle arrest and apoptosis. Cell cycle arrest was associated with decreased activities of the cdc2/cyclin B1 complex, including suppressed expression of cyclin B1, cdc2 and cdc25c, and elevated expression levels of phosphorylated cdc2 (Tyr15). Moreover, CPZ suppressed mitochondrial membrane potential and elevated reactive oxygen species levels in cancer cells, implying that it induces mitochondria-dependent intrinsic apoptosis. CPZ blocked the autophagic flux and induced cytotoxic autophagy in CRC cells. In addition, CPZ suppressed tumor growth in two subcutaneous mouse models without causing obvious side effects. Analysis of the abundance of immune cells in the tumor microenvironment revealed that CPZ did not have an effect on their proportions. Furthermore, it significantly suppressed the lung metastasis of CT26 cells and prolonged mice survival. CONCLUSION: These findings indicated that repurposing CPZ is a novel treatment strategy for CRC patients.
PURPOSE: Despite efforts in developing effective therapeutic strategies, colorectal cancer (CRC) remains one of the most prevalent and lethal neoplasms. Repurposing approved drugs is an alluring strategy for developing anticancer agents. Some antipsychotic drugs, including chlorpromazine (CPZ), possess anticancer activities. However, the pharmacological effects of CPZ on CRC have not been clearly established. METHODS: MTT assay, flow cytometry, western blotting analysis, subcutaneous mice tumor, and tail-vein-injection established lung metastasis model were used to investigate the anticancer effects of CPZ on CRC and the underlying mechanism. RESULTS: We found that CPZ effectively suppressed CRC by inducing G2/M cell cycle arrest and apoptosis. Cell cycle arrest was associated with decreased activities of the cdc2/cyclin B1 complex, including suppressed expression of cyclin B1, cdc2 and cdc25c, and elevated expression levels of phosphorylated cdc2 (Tyr15). Moreover, CPZ suppressed mitochondrial membrane potential and elevated reactive oxygen species levels in cancer cells, implying that it induces mitochondria-dependent intrinsic apoptosis. CPZ blocked the autophagic flux and induced cytotoxic autophagy in CRC cells. In addition, CPZ suppressed tumor growth in two subcutaneous mouse models without causing obvious side effects. Analysis of the abundance of immune cells in the tumor microenvironment revealed that CPZ did not have an effect on their proportions. Furthermore, it significantly suppressed the lung metastasis of CT26 cells and prolonged mice survival. CONCLUSION: These findings indicated that repurposing CPZ is a novel treatment strategy for CRC patients.
Authors: Sudeep Pushpakom; Francesco Iorio; Patrick A Eyers; K Jane Escott; Shirley Hopper; Andrew Wells; Andrew Doig; Tim Guilliams; Joanna Latimer; Christine McNamee; Alan Norris; Philippe Sanseau; David Cavalla; Munir Pirmohamed Journal: Nat Rev Drug Discov Date: 2018-10-12 Impact factor: 84.694