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Tumor Biology

, Volume 37, Issue 6, pp 7589–7597 | Cite as

Oxymatrine synergistically enhances the inhibitory effect of 5-fluorouracil on hepatocellular carcinoma in vitro and in vivo

  • Yan Liu
  • Tingting Bi
  • Wei Dai
  • Gang Wang
  • Liqiang Qian
  • Quangen GaoEmail author
  • Genhai ShenEmail author
Original Article

Abstract

Oxymatrine (OMT), one of the main active components of extracts from the dry roots of Sophora flavescens, has long been employed clinically to treat cancers. Here, we investigated the synergistic effect of OMT with 5-fluorouracil (5-Fu) on the tumor growth inhibition of hepatocellular carcinoma cells (HCC; Hep-G2 and SMMC-7721) and explored the underlying mechanism. Cells were treated with OMT and/or 5-Fu and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay, and immunohistochemistry. OMT and 5-Fu inhibited the proliferation of Hep-G2 and SMMC-7721 cells, and combination treatment with OMT and 5-Fu resulted in a combination index <1, indicating a synergistic effect. Co-treatment with OMT and 5-Fu caused G0/G1 phase arrest by upregulating P21 and P27 and downregulating cyclin D, and induced apoptosis through increasing the production of reactive oxygen species (ROS) and decreasing the levels of p-ERK. In addition, the inhibition of ROS respectively reversed the cell death induced by 5-Fu + OMT, suggesting the key roles of ROS in the process. More importantly, 5-Fu and OMT in combination exhibit much superior tumor weight and volume inhibition on SMMC-7721 xenograft mouse model in comparison to 5-Fu or OMT alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which was consistent with our in vitro results. Taken together, our findings indicated that OMT sensitizes HCC to 5-Fu treatment by the suppression of ERK activation through the overproduction of ROS, and combination treatment with OMT and 5-Fu would be a promising therapeutic strategy for HCC treatment.

Keywords

Oxymatrine Hepatocellular carcinoma 5-Fluorouracil ROS 

Notes

Acknowledgments

This study was supported by the Program for Young Scientist in Science and Education of Suzhou City (No. KJXW2014053) and the Program for Young Scientist in Science and Education of Wujiang District (No. WWK201415).

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.

Ethics approval

The animal studies were approved by the Wujiang No. 1 People’s Hospital Ethics Committee, and the principles of laboratory animal care were followed in all animal experiments.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of General SurgeryWujiang No. 1 People’s HospitalSuzhouChina
  2. 2.Department of Geriatric WardWujiang No. 1 People’s HospitalSuzhouChina

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