Bufalin enhances the anti-proliferative effect of sorafenib on human hepatocellular carcinoma cells through downregulation of ERK |
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Authors: | Yang Gao Hua-Xing Li Li-Tao Xu Peng Wang Li-Yan Xu Lorenzo Cohen Pei-Ying Yang Ke Gu Zhi-Qiang Meng |
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Institution: | (1) Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China;(2) Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, USA;(3) Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA;(4) Department of Radiation Oncology, Suzhou Municipal Hospital (East Branch), 16 West Bai Ta Road, Suzhou, Jiangsu Province, 215001, China;(5) Department of Integrative Medicine, Shanghai Medical School, Fudan University, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China;(6) Present address: Department of Medical Oncology, Tongjiang Hospital, East Nan Guo Road, Shunde District, Foshan, Guangdong, 528000, China; |
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Abstract: | The purpose of this study was to investigate the effect of bufalin on the anti-proliferative activity of sorafenib in the
human hepatocellular carcinoma (HCC) cell lines PLC/PRF/5 and Hep G-2 and to determine the relevant molecular mechanism. Concurrent
treatment with sorafenib and bufalin at a fixed ratio (25:1) for 48 h resulted in synergistic growth inhibition in HCC cell
lines as determined by CCK-8 cell viability assays. Exposure of both PLC/PRF/5 and Hep G-2 cells to this combination of sorafenib
(6.25 μM) and bufalin (50 nM) resulted in noticeable increases in apoptotic cell death, as evidenced by the disruption of
mitochondria, compared to treatment with either agent alone. Although both sorafenib (6.25 μM) and bufalin (250 nM) alone
inhibited the phosphorylation of ERK, the reduction in pERK was more pronounced in the cells treated with a combination of
bufalin (50 nM) and sorafenib (250 nM). Furthermore, the inhibitory effect of bufalin on pERK was blocked by the PI3kinase
inhibitor LY294002, suggesting that the reduction in pERK induced by bufalin might be mediated by AKT in these two HCC cell
lines. Taken together, the results of our study suggest that bufalin enhances the anti-cancer effects of sorafenib on PLC/PRF/5
and Hep G-2 by contributing to the downregulation of ERK. |
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