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Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells: Roles of Apoptosis and Autophagy
Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China
Department of Pharmacy, Chinese PLA General Hospital, Beijing 100850, China
Department of Hand Surgery, 401 Military Hospital, Qingdao 266071, China
Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China
Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 6 November 2012; in revised form: 25 December 2012 / Accepted: 25 December 2012 / Published: 11 January 2013
Abstract: The traditional Chinese medicine bufalin, extracted from toad’s skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type I programmed cell death (PCD). However, type II PCD, or autophagy, participates in cancer proliferation, progression, and relapse, as well. Recent studies on autophagy seem to be controversial because of the dual roles of autophagy in cancer survival and death. In good agreement with previous studies, we found that 100 nM bufalin induced extensive HepG2 cell apoptosis. However, we also noticed bufalin triggered autophagy and enhanced Beclin-1 expression, LC3-I to LC3-II conversion, as well as decreased p62 expression and mTOR signaling activation in HepG2 cells. Blockage of autophagy by selective inhibitor 3-MA decreased apoptotic ratio in bufalin-treated HepG2 cells, suggesting a proapoptotic role of bufalin-induced autophagy. Furthermore, we investigated the underlying mechanisms of bufalin-induced autophagy. Bufalin treatment dose-dependently promoted AMPK phosphorylation while AMPK inhibition by compound C significantly attenuated bufalin-induced autophagy. Taken together, we report for the first time that bufalin induces HepG2 cells PCD, especially for autophagy, and the mechanism of action is, at least in part, AMPK-mTOR dependent.
Keywords: hepatocellular carcinoma; bufalin; apoptosis; autophagy; AMPK; mTOR
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Miao, Q.; Bi, L.-L.; Li, X.; Miao, S.; Zhang, J.; Zhang, S.; Yang, Q.; Xie, Y.-H.; Zhang, J.; Wang, S.-W. Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells: Roles of Apoptosis and Autophagy. Int. J. Mol. Sci. 2013, 14, 1370-1382.
Miao Q, Bi L-L, Li X, Miao S, Zhang J, Zhang S, Yang Q, Xie Y-H, Zhang J, Wang S-W. Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells: Roles of Apoptosis and Autophagy. International Journal of Molecular Sciences. 2013; 14(1):1370-1382.
Miao, Qing; Bi, Lin-Lin; Li, Xin; Miao, Shan; Zhang, Jin; Zhang, Song; Yang, Qian; Xie, Yan-Hua; Zhang, Jian; Wang, Si-Wang. 2013. "Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells: Roles of Apoptosis and Autophagy." Int. J. Mol. Sci. 14, no. 1: 1370-1382.