Potent inhibition of tumoral hypoxia-inducible factor 1alpha 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-1alpha) 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-1alpha. METHOD: In vitro, the effects of ABZ on HIF-1alpha 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-1alpha and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR. RESULTS: In vitro, ABZ inhibited cellular HIF-1alpha 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-1alpha and VEGF. Whereas, tumoral HIF-1alpha and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1alphamRNA) 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-1alpha 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-1alpha surge, tumor invasiveness and metastasis.

The influence of ovarian cancer induced peritoneal carcinomatosis on the pharmacokinetics of albendazole in nude mice.

Angiogenesis in the peritoneal cavity arising from ovarian cancer leads to peritoneal carcinomatosis, malignant ascites formation, morbidity and high mortality. Recent studies in our laboratory have shown albendazole (ABZ) to be a potent inhibitor of angiogenesis and malignant ascites formation. The current study was designed to find the pharmacokinetics of the drug and its major metabolites albendazole sulfoxide (ABZSO) and albendazole sulfone (ABZSO(2)) in an experimental model of ovarian cancer. Additionally, we sought to investigate if the cancer-induced changes in the peritoneal cavity would affect the kinetics of ABZ. On this basis, ABZ was administered 150 mg/kg intraperitoneally to groups of mice bearing peritoneal carcinomatosis and also to groups of healthy mice with no tumor. Blood and peritoneal wash samples were collected for up to 72 h. Concentration of ABZ and its metabolites in the samples were analysed by an established high performance liquid chromatography method. In the healthy mice, drug and metabolite concentrations were found to be low to undetectable. On the contrary, tumor-bearing mice had higher levels of ABZSO in both the plasma and their peritoneal wash. This may at least in part be attributed to the high vascular endothelial growth factor levels present in the peritoneal cavity of the diseased mice. The data obtained in this study suggest that peritoneal carcinomatosis changes ABZ absorption from the peritoneal cavity.