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.


METHODS
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.


CONCLUSIONS
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.
Pourgholami
Mohammad H
MH
Cancer Research Laboratories, University of New South Wales Department of Surgery, St George Hospital, Sydney, NSW 2217, Australia.
Cai
Zhao Y
ZY
Badar
Samina
S
Wangoo
Kiran
K
Poruchynsky
Marianne S
MS
Morris
David L
DL
D015766:Albendazole / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015766:Albendazole; D003676:Deferoxamine
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