glycycoumarin and Liver-Neoplasms

Glycycoumarin (GCM) is a representative of bioactive coumarin compounds isolated from licorice, an edible and medicinal plant widely used for treating various diseases including liver diseases. The purpose of the present study is to examine the possibility of GCM as a sensitizer to improve the efficacy of BH3 mimetic ABT-737 against liver cancer. Three liver cancer cell lines (HepG2, Huh-7 and SMMC-7721) were used to evaluate the in vitro combinatory effect of ABT-737/GCM. HepG2 xenograft model was employed to assess the in vivo efficacy of ABT-737/GCM combination. Results showed that GCM was able to significantly sensitize liver cancer cells to ABT-737 in both in vitro and in vivo models. The enhanced efficacy by the combination of ABT-737 and GCM was attributed to the inactivation of T-LAK cell-originated protein kinase (TOPK)-survivin axis and inhibition of de novo lipogenesis. Our findings have identified induction of TOPK-survivin axis as a novel mechanism rendering cancer cells resistant to ABT-737. In addition, ABT-737-induced platelet toxicity was attenuated by the combination. The findings of the present study implicate that bioactive coumarin compound GCM holds great potential to be used as a novel chemo-enhancer to improve the efficacy of BH3 mimetic-based therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biphenyl Compounds; Coumarins; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Hep G2 Cells; Humans; Inhibitor of Apoptosis Proteins; Lipogenesis; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Nitrophenols; Piperazines; Signal Transduction; Sulfonamides; Survivin; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays

Glycycoumarin (GCM) is a major bioactive coumarin compound isolated from licorice and the anti-cancer activity of GCM has not been scientifically addressed. In the present study, we have tested the anti-liver cancer activity of GCM using both in vitro and in vivo models and found for the first time that GCM possesses a potent activity against liver cancer evidenced by cell growth inhibition and apoptosis induction in vitro and tumor reduction in vivo. Mechanistically, GCM was able to bind to and inactivate oncogenic kinase T-LAK cell-originated protein kinase (TOPK), which in turn led to activation of p53 pathway. Our findings supported GCM as a novel active compound that contributed to the anti-cancer activity of licorice and TOPK could be an effective target for hepatocellular carcinoma (HCC) treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Coumarins; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Protein Conformation; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Licorice, a traditional Chinese medicine, has been used to treat various diseases, including liver disease, for centuries. However, the chemical basis and biological mechanisms underlying the biological functions of licorice remain elusive. The purpose of the current study was to test the hepatoprotective effect of glycycoumarin (GCM), a representative coumarin in licorice, using animal models of both chronic and acute alcoholic liver injury. C57BL/6J mice were used to evaluate the hepatoprotective effect of GCM on liver injury induced by either chronic or acute ethanol exposure. AML-12 and HepG2 cells were utilized to determine the functional role of Nrf2 in the hepatoprotective effect of GCM and to decipher the mechanisms of GCM-induced Nrf2 activation. We found that treatment with GCM leads to a significant reduction in hepatotoxicity in response to either chronic or acute ethanol exposure. Further mechanistic investigations reveal that activation of Nrf2 via the p38 pathway and induction of autophagy by GCM contribute to its hepatoprotective activity. In addition, we demonstrate that p62 upregulation by a transcriptional mechanism also contributes to Nrf2 activation via a positive feedback loop. Our study has identified GCM as a novel active ingredient that contributes to the hepatoprotective activity of licorice.

Topics: Animals; Apoptosis; Autophagy; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Cells, Cultured; Central Nervous System Depressants; Coumarins; Ethanol; Fluorescent Antibody Technique; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger