title: An inhibitor of arachidonate 5-lipoxygenase, Nordy, induces differentiation and inhibits self-renewal of glioma stem-like cells.
abstract: Recent progress in cancer biology indicates that eradication of cancer stem cells (CSCs) is essential for more effective cancer therapy. Unfortunately, cancer stem cells such as glioma stem-like cells (GSLCs) are often resistant to either radio- or chemotherapy. Therefore, screening and development for novel therapeutic modalities against CSCs has been an important emerging field in cancer research. In this study, we report that a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or "Nordy"), inhibited self-renewal and induced differentiation of GSLCs in vitro and in vivo. We found that Nordy inhibited an enzyme known to be involved in leukemia stem cell and leukemia progression, Alox-5, and attenuated the growth of GSLCs in vitro. Nordy reduced the GSLC pool through a decrease in the CD133(+) population and abrogated clonogenicity. Nordy appeared to exert its effect via astrocytic differentiation by up-regulation of GFAP and down-regulation of stemness related genes, rather than by inducing apoptosis of GSLCs. The growth inhibition of xenografted glioma by Nordy was more long-lasting compared with that of the akylating agent BCNU, which exhibited significant relapse on drug discontinuation resulting from an enrichment of GSLCs. Meanwhile, transient exposure to Nordy reduced tumorigenecity of GSLCs and induced differentiation of the xenografts. Taken together, we have identified Alox-5 as a novel target in GSLCs and its inhibition with Nordy exhibits therapeutic implications through inducing GSLC differentiation.
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Shi-cang
authors.initials: SC
authors.lastname: Yu
authors.forename: Jian-yong
authors.initials: JY
authors.lastname: Jiang
authors.forename: Gavin Wallace
authors.initials: GW
authors.lastname: Porter
authors.forename: Lin-tao
authors.initials: LT
authors.lastname: Zhao
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Tan
authors.forename: You-hong
authors.initials: YH
authors.lastname: Cui
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: Yi-fang
authors.initials: YF
authors.lastname: Ping
authors.forename: Xiu-wu
authors.initials: XW
authors.lastname: Bian
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; D019394:Ki-67 Antigen; D016859:Lipoxygenase Inhibitors; C486780:NANOG protein, human; C577484:NES protein, human; D000071317:Nanog Homeobox Protein; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C510003:nordy; D007975:Leukotriene B4; D009637:Masoprocol; D001094:Arachidonate 5-Lipoxygenase; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases
references.citation: N Engl J Med. 2007 Nov 1;357(18):1841-54
references.pmid: 17978293
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Cancer Res. 2003 Sep 15;63(18):5821-8
references.pmid: 14522905
references.citation: Stem Cells. 2009 Jan;27(1):40-8
references.pmid: 18948646
references.citation: Mod Pathol. 2007 Oct;20(10):1061-8
references.pmid: 17660801
references.citation: Cancer Res. 2007 May 1;67(9):4010-5
references.pmid: 17483311
references.citation: Int J Cancer. 2006 Nov 15;119(10):2247-54
references.pmid: 16921484
references.citation: Stem Cells Dev. 2007 Oct;16(5):837-47
references.pmid: 17999604
references.citation: Cancer Metastasis Rev. 2007 Dec;26(3-4):503-24
references.pmid: 17943411
references.citation: Neuropathology. 2006 Apr;26(2):99-106
references.pmid: 16708542
references.citation: Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1651-8
references.pmid: 19423540
references.citation: Clin Neuropathol. 2009 Nov-Dec;28(6):445-52
references.pmid: 19919819
references.citation: Tumour Biol. 2006;27(2):59-70
references.pmid: 16557043
references.citation: Biochem Biophys Res Commun. 2006 Apr 21;342(4):1368-74
references.pmid: 16516855
references.citation: Carcinogenesis. 2006 Sep;27(9):1902-8
references.pmid: 16632477
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6525-30
references.pmid: 18927292
references.citation: Cell. 2009 Aug 21;138(4):645-659
references.pmid: 19682730
references.citation: Mol Cancer Ther. 2006 Nov;5(11):2716-26
references.pmid: 17121918
references.citation: Cancer Cell. 2008 Jan;13(1):69-80
references.pmid: 18167341
references.citation: Neurosurgery. 2006 Feb;58(2):347-54; discussion 347-54
references.pmid: 16462489
references.citation: J Biol Chem. 2007 Mar 2;282(9):6854-62
references.pmid: 17202146
references.citation: Int Immunopharmacol. 2009 Jun;9(6):701-15
references.pmid: 19239926
references.citation: Cell Stem Cell. 2008 Apr 10;2(4):333-44
references.pmid: 18397753
references.citation: Proteomics. 2008 Feb;8(3):484-94
references.pmid: 18232056
references.citation: Biochim Biophys Acta. 2009 Feb;1789(2):99-108
references.pmid: 19022417
references.citation: Cancer Lett. 2008 Jun 28;265(1):124-34
references.pmid: 18343028
references.citation: Ann Oncol. 2006 Nov;17(11):1620-4
references.pmid: 16600978
references.citation: Cell Stem Cell. 2009 Feb 6;4(2):129-40
references.pmid: 19200802
references.citation: Nat Rev Cancer. 2008 Oct;8(10):755-68
references.pmid: 18784658
references.citation: Nat Genet. 2009 Jul;41(7):783-92
references.pmid: 19503090
references.citation: Gastroenterology. 2003 Jan;124(1):57-70
references.pmid: 12512030
references.citation: Cancer Res. 2006 Aug 15;66(16):7843-8
references.pmid: 16912155
references.citation: PLoS One. 2008 Jul 09;3(7):e2637
references.pmid: 18612434
references.citation: Cancer Res. 2006 Oct 1;66(19):9339-44
references.pmid: 16990346
references.citation: Nature. 2008 Jun 19;453(7198):1072-8
references.pmid: 18469801
references.citation: Nat Genet. 2008 May;40(5):499-507
references.pmid: 18443585
references.citation: BMC Cancer. 2007 Jul 25;7:138
references.pmid: 17651499
references.citation: J Neurooncol. 2010 May;97(3):339-46
references.pmid: 19862483