Tumor hypoxia has been classified into two models. Acute, intermittent or cycling hypoxia is associated with inadequate blood flow while chronic hypoxia is the consequence of the increased oxygen diffusion distance due to tumour expansion. It has known for many years that hypoxia renders cells chemoresistant. However, these studies focused mainly on the effects of chronic hypoxia on chemosensitivity. Whether cycling hypoxia plays a vital role in hypoxia-induced chemoresistance and the underlying molecular mechanism of cycling hypoxia-induced drug resistance remains unclear. In the present study, we determined a direct causal link between cycling hypoxia and tumor chemosensitivity in glioma and documented a molecular mechanism in this process. We exposed U87 and U251 cells to experimentally imposed cycling or chronic hypoxic stress in vitro prior to treatment with chemotherapeutic agents, BCNU and temozolomide. TUNEL assay and cell viability assay were performed to determine apoptosis and survival induced by serum deprivation and chemotherapeutic agents. The potential mechanism
was assessed by molecular assay. Our results demonstrated that cycling
hypoxia induces ROS production by NADPH oxidase. These ROS mediate HIF-1 and NF-κB activation and further increase the transactivation of Bcl-xL and attenuation of caspase-3 and -8 activity. Overall mechanisms trigger antiapoptosis and chemoresistance in glioma cells. NF-κB and HIF-1 blockade by NF-κB inhibitor (BAY 11-7082) and HIF-1inhibitor (YC-1) or superoxide scavenger, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxylor4-hydroxy-tempo) suppressed cycling hypoxia induced tumor cell chemoprotective response. Our novel findings suggest that treated ROS scavengers before drug administration and concurrent with chemotherapy may be an effective approach by which to suppress cycling hypoxia-induced chemoresistance and further improve the treatment efficacy of chemotherapy.
