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Hypoxia is associated with resistance to chemotherapy in a number of human cancer types; particularly in hepatocellular carcinoma (HCC), which is a highly vascularized tumor. To develop a potential combination therapy strategy that is capable of overcoming the hypoxia-induced insensitivity to chemotherapy, the HCC cell SMMC-7721 was employed to investigate the hypoxia-induced chemoresistance to etoposide. Increased levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were observed when SMMC-7721 cells were exposed to hypoxia, and exposure of tumor cells to hypoxia impaired etoposide-induced DNA damage, as indicated by the failure of upregulation of γHA2X. Etoposide-induced apoptosis and cell cycle arrest of SMMC-7721 was also impaired in hypoxia. However, co-treatment with anti-VEGF significantly restored etoposide-induced cell apoptosis and cell cycle arrest, as indicated by the elimination of B-cell lymphoma 2 (Bcl-2), procaspase 3, cyclin B1 and Cdc2. Furthermore, anti-VEGF eliminated phosphorylation of AKT, ERK and IκB-α resulting from hypoxia, suggesting the involvement of VEGF in the activation of the survival pathways. In conclusion, the present study suggests a significant role of VEGF in the chemoresistance of etoposide in hypoxia. A rational chemotherapy should be developed based on a combination of etoposide and anti-VEGF. [ABSTRACT FROM AUTHOR]