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Environ Toxicol. 2018 Dec;33(12):1237-1244. doi: 10.1002/tox.22630. Epub 2018 Sep 6.

Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression.

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Department of Laboratory, Chung-Kang Branch, Cheng-Ching General Hospital, Taichung, Taiwan.
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.


To improve the clinical outcome of tumor chemotherapy, more effective combination treatments against tumor metastasis and recurrence are required. Licochalcone A (LicA) is the root of Glycyrrhiza inflata and has been reported to possess anti-inflammatory, antimicrobial, and antitumor effects. Sorafenib (Sor), a multikinase inhibitor, is used to treat patients with solid tumors such as advanced hepatocellular carcinoma (HCC). However, the synergistic effects of LicA and Sor on the metastasis of human HCC cells have not been reported. We found that LicA and Sor did not have cytotoxic effects or arrest growth in human SK-Hep-1 and Huh-7 cells. In addition, treatment with LicA or Sor alone inhibited migration and invasion in human SK-Hep-1 and Huh-7 HCC cells. Furthermore, cotreatment with LicA and Sor synergistically inhibited the migration and invasion of HCC cells and significantly inhibited uPA protein expression. Notably, cotreatment of LicA and Sor synergistically and significantly downregulated MKK4-JNK expression. Through tail vein injection in nude mice, the aforementioned cotreatment synergistically suppressed SK-Hep-1 cell-mediated lung metastasis. These findings first revealed the synergistic effects of LicA and Sor cotreatment against human HCC cells, further suggesting that beneficial effects on tumor regression could be confirmed through prospective clinical trials.


hepatocellular carcinoma cell; invasion; licochalcone A; migration; sorafenib; uPA

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