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.
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Acknowledgments
The authors gratefully acknowledge financial support from National Natural Science Foundation of China (81272473, 81302806), Zhejiang Provincial Foundation of Natural Science (LQ16H310004), Public-Service Technology Research Plan of Zhejiang Province (2015C33269, 2016C33210), High-level Talents Coming Back From Abroad Innovation and Entrepreneurship Program in Hangzhou (2051), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents (2010-190-4), Scientific and Technological Developing Scheme of Hangzhou City (20150733Q14, 20140633B03), Hang-zhou 131 Talents Project.
Funding
This study was funded by National Natural Science Foundation of China (81272473, 81302806), Zhejiang Provincial Foundation of Natural Science (LQ16H310004), Public-Service Technology Research Plan of Zhejiang Province (2015C33269, 2016C33210), High-level Talents Coming Back From Abroad Innovation and Entrepreneurship Program in Hangzhou (2051), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents (2010-190-4), Scientific and Technological Developing Scheme of Hangzhou City (20150733Q14, 20140633B03), Hang-zhou 131 Talents Project.
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Yang-ling Li declares that she has no conflict of interest; Jiao Sun declares that she has no conflict of interest; Xiu Hu declares that she has no conflict of interest; Yi-ni Pan declares that she has no conflict of interest; Wei Yan declares that she has no conflict of interest; Qing-yu Li declares that she has no conflict of interest; Fei Wang declares that he has no conflict of interest; Neng-ming Lin declares that he has no conflict of interest; Chong Zhang declares that he has no conflict of interest.
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This article does not contain any studies with human participants performed by any of the authors. This article does not contain any studies with animals performed by any of the authors.
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Li, Yl., Sun, J., Hu, X. et al. Epothilone B induces apoptosis and enhances apoptotic effects of ABT-737 on human cancer cells via PI3K/AKT/mTOR pathway. J Cancer Res Clin Oncol 142, 2281–2289 (2016). https://doi.org/10.1007/s00432-016-2236-y
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DOI: https://doi.org/10.1007/s00432-016-2236-y