Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole

Background: Emerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1 alpha) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1 alpha. Method: In vitro, the effects of ABZ on HIF-1 alpha levels in human ovarian cancer cells (OVCAR-3) were investigated using hypoxic chamber or desferrioxamine (DFO) induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose) on the tumor levels of HIF-1 alpha and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR. Results: In vitro, ABZ inhibited cellular HIF-1 alpha protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1 alpha and VEGF. Whereas, tumoral HIF-1 alpha and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGF-mRNA (but not HIF-1 alpha-mRNA) was also found to be highly suppressed by ABZ. Conclusion: These results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1 alpha and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1 alpha surge, tumor invasiveness and metastasis.