EGF Reverses Multi-drug Resistance via the p-ERK Pathway in HepG2/ADM and SMMC7721/ADM Hepatocellular Carcinoma Models

Abstract

Aim: To investigate signaling pathways for reversal of EGF-mediated multi-drug resistance (MDR) inhepatocellular carcinoma (HCC) models. Materials and <br/><b>Methods</b>: HCC MDR cell strain HepG2/adriamycin(ADM) and SMMC7721/ADM models were established using a method of exposure to medium with ADMbetween low and high concentration with gradually increasing concentration. Drug sensitivity and reversalof multi-drug resistance by EGF were determined and the cell cycle distribution and apoptosis were analyzedby flow cytometry. Phosphorylation of ERK1, ERK2, ERK5 and expression of Bim were detected by Westernblotting. <br/><b>Results</b>: The results showed that HepG2/ADM and SMMC7721/ADM cells were resistant not only toADM, but also to multiple anticancer drugs. When used alone, EGF had no anti-tumor activity in HepG2/ADMand SMMC7721/ADM cells in vitro, while it increased the cytotoxicity of ADM. EGF induced cell apoptosis andG0/G1 phase cell cycle arrest in HepG2/ADM And SMMC7721/ADM cells, while enhancing activity of p-ERKsand up-regulated expression of BimEL. <br/><b>Conclusions</b>: EGF might enhance the chemosensitivity of HepG2/ADMand SMMC7721/ADM cells via up-regulating p-ERKs and BimEL protein.