title: Potent inhibition of tumoral hypoxia-inducible factor 1alpha by albendazole.
abstract: 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.
authors.affiliation: Cancer Research Laboratories, University of New South Wales Department of Surgery, St George Hospital, Sydney, NSW 2217, Australia.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Pourgholami
authors.forename: Zhao Y
authors.initials: ZY
authors.lastname: Cai
authors.forename: Samina
authors.initials: S
authors.lastname: Badar
authors.forename: Kiran
authors.initials: K
authors.lastname: Wangoo
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Poruchynsky
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
mesh_terms: 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
chemical_list: 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
references.citation: Mol Cell Biol. 1996 Sep;16(9):4604-13
references.pmid: 8756616
references.citation: Oncology. 2005;69 Suppl 3:11-6
references.pmid: 16301831
references.citation: IUBMB Life. 2008 Sep;60(9):591-7
references.pmid: 18506846
references.citation: Cancer Metastasis Rev. 2007 Jun;26(2):281-90
references.pmid: 17603752
references.citation: Cancer Invest. 2009 Feb;27(2):171-7
references.pmid: 19235589
references.citation: Cancer Res. 2004 Mar 15;64(6):2054-61
references.pmid: 15026343
references.citation: N Engl J Med. 1971 Nov 18;285(21):1182-6
references.pmid: 4938153
references.citation: Clin Cancer Res. 2002 Sep;8(9):2963-9
references.pmid: 12231542
references.citation: N Engl J Med. 2008 May 8;358(19):2039-49
references.pmid: 18463380
references.citation: FASEB J. 2005 Aug;19(10):1308-10
references.pmid: 15941769
references.citation: Nat Rev Cancer. 2003 Oct;3(10):721-32
references.pmid: 13130303
references.citation: Clin Cancer Res. 2006 Mar 15;12(6):1928-35
references.pmid: 16551879
references.citation: Clin Cancer Res. 2007 Oct 1;13(19):5670-4
references.pmid: 17908955
references.citation: Cancer Cell. 2009 Mar 3;15(3):232-9
references.pmid: 19249681
references.citation: Mol Cancer Ther. 2002 Nov;1(13):1201-9
references.pmid: 12479701
references.citation: Cancer Chemother Pharmacol. 2005 May;55(5):425-32
references.pmid: 15565325
references.citation: Cancer Chemother Pharmacol. 2008 Apr;61(5):809-17
references.pmid: 17581752
references.citation: Cancer Cell. 2008 Mar;13(3):206-20
references.pmid: 18328425
references.citation: Cancer Metastasis Rev. 2000;19(1-2):59-65
references.pmid: 11191064
references.citation: Mol Cancer Res. 2006 Sep;4(9):601-5
references.pmid: 16940159
references.citation: Oncology. 2001;61(1):42-6
references.pmid: 11474247
references.citation: Int J Parasitol. 1988 Nov;18(7):885-936
references.pmid: 3066771
references.citation: Cancer Cell. 2009 Mar 3;15(3):220-31
references.pmid: 19249680
references.citation: Curr Opin Infect Dis. 2002 Dec;15(6):599-608
references.pmid: 12821837
references.citation: Drug Discov Today. 2007 Oct;12(19-20):853-9
references.pmid: 17933687
references.citation: Eur J Cancer. 2009 May;45(7):1117-1128
references.pmid: 19124237
references.citation: Cell Tissue Res. 2009 Jan;335(1):261-9
references.pmid: 18766380
references.citation: Cancer Cell. 2003 Apr;3(4):347-61
references.pmid: 12726861
references.citation: Cancer Cell. 2005 Oct;8(4):299-309
references.pmid: 16226705
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6371-5
references.pmid: 18927275
references.citation: Science. 2001 Apr 20;292(5516):468-72
references.pmid: 11292861
references.citation: Oncology. 2005;69 Suppl 3:4-10
references.pmid: 16301830
references.citation: Exp Cell Res. 2005 May 15;306(1):274-84
references.pmid: 15878351
references.citation: Cancer Cell. 2009 Jan 6;15(1):3-5
references.pmid: 19111874
references.citation: Nat Rev Drug Discov. 2007 Apr;6(4):273-86
references.pmid: 17396134
references.citation: Biochem Pharmacol. 2007 Aug 1;74(3):407-14
references.pmid: 17560963
references.citation: Trends Pharmacol Sci. 2009 Dec;30(12):624-30
references.pmid: 19836845
references.citation: Vet Parasitol. 1987 Jan;23(1-2):105-19
references.pmid: 3564338
references.citation: Nature. 1992 Oct 29;359(6398):843-5
references.pmid: 1279431
references.citation: Cancer Lett. 2001 Apr 10;165(1):43-9
references.pmid: 11248417