Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma
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Yu-Jen Chen1,2,3,4, Chih-Wen Chi1, Wen-Chi Su5,6 and Huey-Lan Huang7
1 Department of Medical Research Mackay Memorial Hospital, Taipei, Taiwan
2 Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan
3 Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
4 Institute of Pharmacology, Taipei Medical University, Taipei, Taiwan
5 Research Center for Emerging Viruses, China Medical University Hospital, Taichung, Taiwan
6 China Medical University, Taichung, Taiwan
7 Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan
Huey-Lan Huang, email:
Keywords: lapatinib, autophagy, hepatoma, cell death
Received: May 01, 2014 Accepted: May 30, 2014 Published: May 31, 2014
Lapatinib, an orally adminstered small-molecule tyrosine kinase inhibitor targeting epidermal growth factor receptors (EGFR) and Her2/Neu, has been widely accepted in the treatment of breast cancer. In this study, we found that lapatinib induced cytotoxicity in human hepatoma Huh7, HepG2 and HA22T cells. For the mode of cell death, we found lapatinib induced a higher percent of dead cells and a lower percent of hypodiploid cells, suggesting non-apoptotic cell death in lapatinib-treated hepatoma cells. Moreover, lapatinib-induced autophagy in hepatoma cells was confirmed by the detection of autophagic LC3-II conversion, the up-regulation of autophagy-related proteins, and the down-regulation of p62 by immunoblotting. Autophagic cell death was demonstrated by images of punctuated LC3 patterns, a higher percent of acridine orange positive cells, as well as a partial rescue of cell death by autophagy inhibitor 3-methyladenine or chloroquine. We also found massive vacuoles in lapatinib-treated hepatoma cells by electronic microscopy. In addition, the shRNA of knocked-down autophagy-related proteins rescued the hepatoma cells from lapatinib-induced growth inhibition. We also demonstrated a reduction of tumorigenesis by lapatinib in vivo. In conclusion, lapatinib induced autophagic cell death and the growth of human hepatoma cells. Our study provides potential cancer therapies by using lapatinib as a treatment for hepatoma.
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