Tyrosine kinase inhibitor Thiotanib targets Bcr-Abl and induces apoptosis and autophagy in human chronic myeloid leukemia cells
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- 作者：Jiajun Fan (1)
Xiaochun Dong (1)
Weixing Zhang (1)
Xian Zeng (1)
Yubin Li (1)
Yun Sun (1)
Shaofei Wang (1)
Ziyu Wang (1)
Hongjian Gao (1)
Weili Zhao (1) (2)
Dianwen Ju (1) - 关键词：Chronic myeloid leukemia ; Bcr ; Abl ; Tyrosine kinase inhibitor ; Compound Thiotanib ; Apoptosis ; Autophagy
- 刊名：Applied Microbiology and Biotechnology
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：98
- 期：23
- 页码：9763-9775
- 全文大小：3,860 KB
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Xiaochun Dong (1)
Weixing Zhang (1)
Xian Zeng (1)
Yubin Li (1)
Yun Sun (1)
Shaofei Wang (1)
Ziyu Wang (1)
Hongjian Gao (1)
Weili Zhao (1) (2)
Dianwen Ju (1)
1. School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People’s Republic of China
2. Key Laboratory for Special Functional Materials of the Ministry of Education, Henan University, Kaifeng, 475004, People’s Republic of China - ISSN：1432-0614
文摘
Chronic myeloid leukemia (CML) is characterized by abnormal Bcr and Abl genes and enhanced tyrosine kinase activity. Anti-CML therapy has been much improved along with the applications of tyrosine kinase inhibitors (TKIs) which selectively target Bcr-Abl and have a cytotoxic effect on CML. Recently, four-membered heterocycles as “compact modules-have attracted much interest in drug discovery. Grafting these small four-membered heterocycles onto a molecular scaffold could probably provide compounds that retain notable activity and populate chemical space otherwise not previously accessed. Accordingly, a novel TKI, Thiotanib, has been designed and synthesized. It selectively targets Bcr-Abl, inducing growth inhibition, cell cycle arrest, and apoptosis of CML cells. Meanwhile, the compound Thiotanib could also induce autophagy in CML cells. Interestingly, inhibition of autophagy promotes Thiotanib-induced apoptosis with no further activation of caspase 3, while inhibition of caspases did not affect the cell survival of CML cells. Moreover, the compound Thiotanib could inhibit phosphorylation of Akt and mTOR, increase beclin-1 and Vps34, and block the formation of the Bcl-2 and Beclin-1 complex. This indicates the probable pathway of autophagy initiation. Our results highlight a new approach for TKI reforming and further provide an indication of the efficacy enhancement of TKIs in combination with autophagy inhibitors.