BMB Reports 2018; 51(9): 474-479  https://doi.org/10.5483/BMBRep.2018.51.9.114
Resveratrol enhances cisplatin-induced apoptosis in human hepatoma cells via glutamine metabolism inhibition
Zhaoyuan Liu1, Qing Peng1, Yang Li1 & Yi Gao1,2,*
1Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, 2State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
Correspondence to: Tel: +86-0206143207; Fax: +86-02061432; E-mail: drgaoy@126.com
Received: May 23, 2018; Revised: June 23, 2018; Accepted: August 8, 2018; Published online: September 30, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Cisplatin is one of the most effective chemotherapeutic drugs used in the treatment of HCC, but many patients will ultimately relapse with cisplatin-resistant disease. Used in combination with cisplatin, resveratrol has synergistic effect of increasing chemosensitivity of cisplatin in various cancer cells. However, the mechanisms of resveratrol enhancing cisplatin-induced toxicity have not been well characterized. Our study showed that resveratrol enhances cisplatin toxicity in human hepatoma cells via an apoptosis-dependent mechanism. Further studies reveal that resveratrol decreases the absorption of glutamine and glutathione content by reducing the expression of glutamine transporter ASCT2. Flow cytometric analyses demonstrate that resveratrol and cisplatin combined treatment leads to a significant increase in ROS production compared to resveratrol or cisplatin treated hepatoma cells alone. Phosphorylated H2AX (γH2AX) foci assay demonstrate that both resveratrol and cisplatin treatment result in a significant increase of γH2AX foci in hepatoma cells, and the resveratrol and cisplatin combined treatment results in much more γH2AX foci formation than either resveratrol or cisplatin treatment alone. Furthermore, our studies show that over-expression of ASCT2 can attenuate cisplatin-induced ROS production, γH2AX foci formation and apoptosis in human hepatoma cells. Collectively, our studies suggest resveratrol may sensitize human hepatoma cells to cisplatin chemotherapy via glutamine metabolism inhibition.
Keywords: Apoptosis, Cisplatin, Glutaminolysis, Human hepatoma cells, Resveratrol


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