Department of Respiratory Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China; Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China.
Int J Cancer. 2012 Feb 23. doi: 10.1002/ijc.27504.
The pan-Src family kinase inhibitor dasatinib has been approved for chronic myeloid leukemia treatment but displays limited activity in lung cancer patients. In this study, we used a deuterium substitution strategy to develop a class of novel chemicals based on dasatinib and found that these compounds maintain inhibition on c-Src activity and display anti-non-small cell lung cancer activity in vitro and in vivo. BRP800, one of these compounds, was chosen for further studies. BRP800 mainly displayed anti-proliferative but not pro-apoptotic activity. Molecularly, BRP800 did not show significant effects on the expression of anti-apoptotic genes, such as Bcl-2 and Mcl1, or on the activation of apoptotic enzymes, such as caspase-3, -8 or 9. However, BRP800 decreased expression of cell cycle promoting genes such as cyclins D1, D3, E, A, and CDK4, and 6, and increased the expression of cell cycle negative regulators including p21, p27 and p53. Consistent with these findings, BRP800 arrested cells at the G0/G1 phase in a concentration-dependent manner, and the G0/G1 fraction was increased from 64% in control to 85% in BRP800-treated cells. We also evaluated the effects of BRP800 on NSCLC xenografts using H460 as a model in nude mice. Compared with the known NSCLC drug docetaxel, BRP800 displayed potent and similar anti-tumor activity but with less toxicity. These findings suggest that the deuterated analog of dasatinib is anti-proliferative by inhibiting c-Src and disrupting cell cycle progression, and could be further developed as a novel drug for non-small lung cancer treatment. © 2012 Wiley-Liss, Inc.
Copyright © 2012 UICC.
PMID: 22362357 [PubMed - as supplied by publisher] Source: National Library of Medicine.
