Mechanism of Hypoxia-inducible Factor-1α Inducing Drug Resistance to Oxaliplatin in Hepatic Carcinoma

Objective To investigate the potential mechanism of hypoxia microenvironment, hypoxiainducible factor-1α and multidrug resistance gene inducing drug resistance to oxaliplatin in hepatic carcinoma (HepG2/oxal). Methods A resistant cell line HepG2/oxal were established by increasing dose of oxaliplatin from 2.5 to 5.0 μg/ml. The intracellular reactive oxygen species(ROS) and cell apoptosis rates were detected by flow cytometry. mRNA and protein levels of HIF- 1α and multidrug-resistance proteins, MDR1, MRP1 and BCRP were detected by RT-PCR and Western blot. Results With the increasing resistance drug dose, intracellular ROS and apoptosis rates were decreased, mRNA contents of HIF-1α, MDR1, MRP1, BCRP were increased, and the protein levels were as same as mRNA levels HepG2/oxal cells. Conclusion Hypoxia microenvironment is a significant reason for drug resistance to oxaliplatin in hepatic carcinoma. Hypoxia could modulate the expression of multidrug-resistance genes, MDR1, MRP1 and BCRP1, and the apoptosis tolerance via upregulating HIF-1α expression, which may cause the acquired resistance to oxaliplatin in hepatic carcinoma.