Yang-Ling Li1, Jiao Sun2, Xiu Hu3,4, Yi-Ni Pan3, Wei Yan1, Qing-Yu Li1, Fei Wang1, Neng-Ming Lin5,6, Chong Zhang7. 1. Department of Clinical Pharmacology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China. 2. Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China. 3. School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China. 4. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China. 5. Department of Clinical Pharmacology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China. lnm1013@163.com. 6. Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China. lnm1013@163.com. 7. School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China. zhangchong@zucc.edu.cn.
Abstract
PURPOSE: Epothilone B and its derivatives are tested in multiple clinical trials. Epothilone B induces neurotoxic effect in clinical trials; however, low-dose epothilone B regimen can promote neuroprotection and neurogenesis. Thus, the study of new combination chemotherapy regimen incorporating low-dose epothilone B with other chemotherapeutic agents might help to develop epothilone B-based approaches to cancer treatment and avoid the neurotoxicity of epothilone B. METHODS: Cell proliferation was assessed by SRB cell viability assay. Apoptosis was analyzed by propidium iodide (PI) staining. Mitochondrial membrane depolarization was evaluated using JC-1 staining. The expression of proteins was detected by western blotting. RESULTS: In this study, we demonstrated that the combination of ABT-737 and low-dose epothilone B showed synergistic anti-proliferation effects on human cancer cells. In addition, epothilone B + ABT-737 synergy was through mitochondria-mediated apoptosis pathway. Furthermore, combination treatment markedly induced the activation of caspase-3 and the cleavage of PARP. The activation of PI3K/Akt/mTOR pathway is associated with resistance to epothilone B. Our data showed that epothilone B plus ABT-737 resulted in a blockade of the PI3K/AKT/mTOR signaling pathway. CONCLUSIONS: These data indicate that ABT-737 may be a pertinent sensitizer to epothilone B, and the strategy of combining epothilone B with ABT-737 appears to be an attractive option for overcoming the resistance and neurotoxicity of epothilone B.
PURPOSE:Epothilone B and its derivatives are tested in multiple clinical trials. Epothilone B induces neurotoxic effect in clinical trials; however, low-dose epothilone B regimen can promote neuroprotection and neurogenesis. Thus, the study of new combination chemotherapy regimen incorporating low-dose epothilone B with other chemotherapeutic agents might help to develop epothilone B-based approaches to cancer treatment and avoid the neurotoxicity of epothilone B. METHODS: Cell proliferation was assessed by SRB cell viability assay. Apoptosis was analyzed by propidium iodide (PI) staining. Mitochondrial membrane depolarization was evaluated using JC-1 staining. The expression of proteins was detected by western blotting. RESULTS: In this study, we demonstrated that the combination of ABT-737 and low-dose epothilone B showed synergistic anti-proliferation effects on humancancer cells. In addition, epothilone B + ABT-737 synergy was through mitochondria-mediated apoptosis pathway. Furthermore, combination treatment markedly induced the activation of caspase-3 and the cleavage of PARP. The activation of PI3K/Akt/mTOR pathway is associated with resistance to epothilone B. Our data showed that epothilone B plus ABT-737 resulted in a blockade of the PI3K/AKT/mTOR signaling pathway. CONCLUSIONS: These data indicate that ABT-737 may be a pertinent sensitizer to epothilone B, and the strategy of combining epothilone B with ABT-737 appears to be an attractive option for overcoming the resistance and neurotoxicity of epothilone B.
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