2. Academic Validation
  3. Suppression of LSD1 enhances the cytotoxic and apoptotic effects of regorafenib in hepatocellular carcinoma cells

Suppression of LSD1 enhances the cytotoxic and apoptotic effects of regorafenib in hepatocellular carcinoma cells

  • Biochem Biophys Res Commun. 2019 May 14;512(4):852-858. doi: 10.1016/j.bbrc.2019.03.154.
Lin-Wen Wu 1,  Dong-Mei Zhou 2,  Zuo-Yan Zhang 1,  Jian-Kang Zhang 1,  Hua-Jian Zhu 1,  Neng-Ming Lin 3,  Chong Zhang 4
Affiliations

Affiliations

  • 1 School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 Department of Clinical Pharmacy, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China; Department of Clinical Pharmacology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
  • 3 Department of Clinical Pharmacy, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China; Department of Clinical Pharmacology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. Electronic address: lnm1013@163.com.
  • 4 School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: zhangchong@zucc.edu.cn.
PMID: 30929918 DOI: 10.1016/j.bbrc.2019.03.154
Abstract

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.

Keywords

AKT; Combination; Hepatocellular carcinoma; LSD1; Regorafenib; Tranylcypromine.

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