Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 512, Issue 4, Pages 852-858Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2019.03.154
Keywords
Regorafenib; LSD1; Hepatocellular carcinoma; ART; Tranylcypromine; Combination
Categories
Funding
- Teachers Research Fund of Zhejiang University City College [J-19006]
- Hangzhou Major Science and Technology Project [2017] [20172016A01]
- Zhejiang Provincial Foundation of Natural Science [LY19H310004]
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Regorafenib has been approved to treat patients who have HCC progression after sorafenib failure, however, regorafenib also faces the risk of drug resistance and subsequent progression of HCC patients. As LSD1 inhibitors can alleviate acquired resistance to sorafenib, in this context, we are interested to investigate the role of LSD1 in regorafenib treatment. Firstly, over-expressed LSD1 was observed in HCC patients and predicted poor prognosis. However, regorafenib failed to suppress the expression of LSD1 in HCC cells. Thus, we hypothesized that LSD1 inhibition could enhance the anti-HCC activity of regorafenib. As expected, LSD1 knockdown could enhance anti-proliferation effect of regorafenib in HCC cells. LSD1 inhibitor SP2509 could enhance the cytotoxic and apoptotic effects of regorafenib in HCC cells. In addition, clinically used LSD1 inhibitor tranylcypromine also enhanced anti-HCC effect of regorafenib. Furthermore, LSD1 suppressed by SP2590 or tranylcypromine could alleviate the activated p-AKT (ser473) induced by regorafenib in HCC cells. Thus, inhibiting LSD1 might be an attractive target for regorafenib sensitization and clinical HCC therapy, our findings could help to elucidate more effective therapeutic options for HCC patients. (C) 2019 Elsevier Inc. All rights reserved.
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