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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]

Abstract  Tumor hypoxia has been reported to be a negative prognostic factor in a number of tumor sites, which suggests a positive correlation between tumor hypoxia and increased metastatic efficiency. Evidence shows that vascular endothelial growth factor (VEGF) stimulates angiogenesis in tumor growth and mediates neuroprotection to prevent an apoptotic cell death. Human neuroblastoma cells (CHP126) were exposed to moderate hypoxia for different time spans to explore the molecular stress responses. Apoptotic features as an increase of Bax/Bcl-2 ratio and activation of caspase 3 were observed at early period of exposure time, but these effects were reversed with the extension of hypoxic treatment. Hypoxia also activated MAPKs signaling pathways in a time-relative manner, which were involved in the regulation of hypoxia-related resistance of CHP126 cells. Meanwhile, VEGF and its receptor KDR were found to interact with MAPKs signaling pathways except the effect of hypoxia. Furthermore, rhVEGF165 was utilized to discern that VEGF increased Bcl-2 and procaspase 3 expressions, contributing to a synergistic relationship of an angiogenic response with Bcl-2 in hypoxia via a cross talk, while the activation of ERK MAPK is important for both productions. These altered signals may be critical to predict a poor outcome; therefore, our knowledge provides new insight into apoptosis and angiogenesis control of tumor cells and suggests a strategy based on the blockade of hypoxia-induced VEGF signaling under hypoxia in neuroblastoma. [ABSTRACT FROM AUTHOR]