Ascochlorin overcomes chemoresistance and regulates the plasticity of doxorubicin induced EMT via modulation of the NF-кB pathway in hepatocellular carcinoma

OBJECTIVE Doxorubicin-based therapy has been found to be not significantly effective for the treatment of advanced stage hepatocellular carcinomas(HCCs),which often undergo epithelial-mesenchymal transition(EMT)during tumor progression.Increasing evidence suggest(s)that epithelial cell transformation to mesenchymal state canenhance the ability to self-renew and confer greater resistance to the conventional chemotherapeutic drugs.The aim of this study was to examine the potential efficacyof ascochlorin,an isoprenoid antibiotic to overcome drug resistance induced by doxorubicin in HCC cell lines and to elucidate its underlying mechanism(s)of action.METHODS The effect of doxorubicin and ascochlorin on HCC cell lines was determined by MTT,Western blotting,immunofluorescence and NF-кB DNA binding assays.RESULTS Our results indicate that HCC cells that show a mesenchymal-like phenotype,are resistance to the doxorubicin therapy which directly correlated with an increased slug expression.We also observed that activation of NF-кB pathway plays an essential role in doxorubicin induced-chemoresistance and pharmacological inhibition of this pathway with ascochlorin can significantly reverse drug-induced invasion/migration and resistance in HCC cells.CONCLUSION Our results indicate that combination treatment of doxorubicin with ascochlorin has the potential to inhibit HCC growth and metastasis.