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Caffeine enhances the anti-tumor effect of 5-fluorouracil via increasing the production of reactive oxygen species in hepatocellular carcinoma

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Abstract

The development of drug resistance affecting the prognosis of patients with hepatocellular carcinoma (HCC) leads to low survival rate of HCC patients. Caffeine is reported to have a function of protecting the liver and anti-tumor activity. Therefore, caffeine may be an ideal enhancer for HCC chemotherapy regimens. Our study showed that the combination of caffeine and 5-FU significantly inhibited the proliferation of HCC cells in vivo and in vitro comparing with caffeine or 5-FU monotherapy. The CI values of caffeine (0.5 mM) combined with 5-FU (25, 50 μM) were all less than 1, confirming that the utilization of drug combination has a synergistic inhibitory effect on the proliferation of HCC cells. Meanwhile, results of Western blot and TUNEL assays demonstrated that the apoptotic level of HCC cells in the combined group was significantly increased. The protein expression level of cleaved PARP was up-regulated, while the protein level of Bcl-2 and Bcl-xL was down-regulated. In addition, we found that ROS levels were increased in the 1 mM caffeine and 25 μM 5-FU combination group comparing with the control or single drug group. Taken together, this is the first study to demonstrate that the combination of caffeine and 5-FU inhibits HCC cells proliferation and promotes cellular apoptosis by regulating intracellular ROS production. The present data provides a basis for the application of caffeine combined with 5-FU as a novel chemotherapy regimen for HCC.

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Funding

This study was supported by Grants from Guangzhou Medical University Student Science and Technology Innovation Project (Grant No. 2017A027), the Science and Technology Program of Guangzhou (Grant No. 201707010470), and the National Natural Science Foundation of China (Grant No. 81372634) and the Guangdong Natural Science Funds for Distinguished Young Scholar (Grant No. S2013050014121).

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Authors and Affiliations

  1. Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, Guangdong, People’s Republic of China

    Zhilei Wang, Chengxin Gu, Kunyuan Wang & Hui Yang

  2. The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, 510260, Guangdong, People’s Republic of China

    Xinrui Wang, Yating Lang, Yanqin Wu, Xiaoqin Wu & Xifei Zhu

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  1. Zhilei Wang
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  2. Chengxin Gu
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  3. Xinrui Wang
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  4. Yating Lang
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  5. Yanqin Wu
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  6. Xiaoqin Wu
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  7. Xifei Zhu
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  8. Kunyuan Wang
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  9. Hui Yang
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Contributions

ZW generated, analyzed, and interpretated the data and prepared the manuscript. CG, XW, YL, YW, XW, and XZ generated, analyzed, and interpretated the data. KW generated the idea, designed the study, analyzed and interpretated the data, and prepared the manuscript. HY generated the idea, designed the study, analyzed and interpretated the data, and edited the manuscript.

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Correspondence to Kunyuan Wang or Hui Yang.

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Wang, Z., Gu, C., Wang, X. et al. Caffeine enhances the anti-tumor effect of 5-fluorouracil via increasing the production of reactive oxygen species in hepatocellular carcinoma. Med Oncol 36, 97 (2019). https://doi.org/10.1007/s12032-019-1323-8

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