title: The implications of hyponitroxia in cancer.
abstract: Tumors are spatially heterogeneous, with regions of relative hypoxia and normoxia. The tumor microenvironment is an important determinant of both tumor growth and response to a variety of cytotoxic and targeted therapies. In the tumor microenvironment, reactive oxygen species and nitric oxide (NO) are important mediators of the level of expression of many transcription factors and signaling cascades that affect tumor growth and responses to therapy. The primary objective of this review is to explore and discuss the seemingly dichotomous actions of NO in cancer biology as both a tumor promoter and suppressor with an emphasis on understanding the role of persistently low NO concentrations or hyponitroxia as a key mediator in tumor progression. This review will also discuss the potential role of hyponitroxia as a novel therapeutic target to treat cancer and outline an approach that provides new opportunities for pharmacological intervention.
authors.affiliation: RadioRx, Inc., Mountain View, CA, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
authors.affiliation: RadioRx, Inc., Mountain View, CA, USA.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Fanger
authors.affiliation: CFLS, San Jose, CA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Oronsky
authors.affiliation: Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Knox
authors.affiliation: RadioRx, Inc., Mountain View, CA, USA. Electronic address: jscicinski@radiorx.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
references.citation: PLoS One. 2011;6(5):e20147
references.pmid: 21647438
references.citation: J Immunol. 1998 Jun 15;160(12):5729-34
references.pmid: 9637481
references.citation: Free Radic Biol Med. 1998 Sep;25(4-5):392-403
references.pmid: 9741578
references.citation: J Immunol. 2011 Jun 15;186(12):6972-80
references.pmid: 21555530
references.citation: PLoS Biol. 2007 Feb;5(2):e38
references.pmid: 17298177
references.citation: Transl Oncol. 2010 Dec 01;3(6):380-8
references.pmid: 21151477
references.citation: Theranostics. 2013 May 25;3(6):437-47
references.pmid: 23781290
references.citation: Pharmacol Rev. 1991 Jun;43(2):109-42
references.pmid: 1852778
references.citation: Hum Exp Toxicol. 2010 Apr;29(4):249-61
references.pmid: 20332169
references.citation: J Exp Med. 1995 Apr 1;181(4):1333-43
references.pmid: 7535333
references.citation: J Natl Cancer Inst. 2001 Dec 19;93(24):1879-85
references.pmid: 11752013
references.citation: Mol Cell Biol. 2010 Oct;30(20):4901-21
references.pmid: 20696840
references.citation: Jpn J Cancer Res. 1997 Dec;88(12):1190-8
references.pmid: 9473737
references.citation: Cell Cycle. 2009 Mar 1;8(5):725-30
references.pmid: 19221483
references.citation: Int J Clin Lab Res. 1994;24(2):94-7
references.pmid: 7919435
references.citation: Cancer Res. 2002 Mar 15;62(6):1876-83
references.pmid: 11912168
references.citation: Circ Res. 2002 Jan 11;90(1):21-8
references.pmid: 11786514
references.citation: Pharmacol Rev. 2000 Sep;52(3):375-414
references.pmid: 10977868
references.citation: Transl Oncol. 2011 Aug;4(4):189-98
references.pmid: 21804913
references.citation: J Biol Chem. 1995 Sep 8;270(36):21195-8
references.pmid: 7673152
references.citation: Int J Cell Biol. 2012;2012:762825
references.pmid: 22666258
references.citation: Nature. 2012 Nov 15;491(7424):364-73
references.pmid: 23151579
references.citation: Int J Cancer. 2004 May 1;109(5):768-73
references.pmid: 14999787
references.citation: J Biol Chem. 2013 May 31;288(22):16004-15
references.pmid: 23546878
references.citation: J Clin Invest. 1993 Feb;91(2):437-42
references.pmid: 7679408
references.citation: Cell Cycle. 2011 Feb 15;10(4):619-24
references.pmid: 21293193
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13147-52
references.pmid: 16141331
references.citation: Lancet Oncol. 2007 Feb;8(2):111-8
references.pmid: 17267325
references.citation: Cancer Metastasis Rev. 1998 Mar;17(1):1-6
references.pmid: 9544419
references.citation: J Immunol. 2009 Jan 1;182(1):259-73
references.pmid: 19109157
references.citation: Pharmacol Ther. 2009 Sep;123(3):344-52
references.pmid: 19464317
references.citation: Transl Oncol. 2008 Dec;1(4):158-64
references.pmid: 19043526
references.citation: J Exp Med. 1999 Dec 6;190(11):1595-604
references.pmid: 10587350
references.citation: Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1155-62
references.pmid: 17276618
references.citation: Cell Res. 2002 Dec;12(5-6):311-20
references.pmid: 12528889
references.citation: J Biol Chem. 2002 Sep 13;277(37):34223-8
references.pmid: 12091382
references.citation: Nat Rev Cancer. 2006 Jul;6(7):521-34
references.pmid: 16794635
references.citation: Circ Res. 2008 Apr 25;102(8):873-87
references.pmid: 18436802
references.citation: Cardiovasc Res. 2004 Jul 1;63(1):1-4
references.pmid: 15194454
references.citation: Crit Rev Toxicol. 2001 Jul;31(4-5):489-501
references.pmid: 11504176
references.citation: J Clin Invest. 1998 Feb 15;101(4):731-6
references.pmid: 9466966
references.citation: Cardiovasc Res. 1999 Aug 15;43(3):521-31
references.pmid: 10690324
references.citation: J Clin Oncol. 2006 Feb 1;24(4):688-94
references.pmid: 16446342
references.citation: Drug Metab Dispos. 2012 Sep;40(9):1810-6
references.pmid: 22699395
references.citation: J Natl Cancer Inst. 2010 Oct 20;102(20):1536-46
references.pmid: 20858887
references.citation: Placenta. 2011 Dec;32(12):932-40
references.pmid: 21962305
references.citation: Nat Med. 2008 Mar;14(3):255-7
references.pmid: 18278052
references.citation: Cancer. 1998 May 15;82(10):1897-903
references.pmid: 9587122
references.citation: Med Res Rev. 2007 May;27(3):317-52
references.pmid: 16991100
references.citation: Transl Oncol. 2012 Jun;5(3):133-40
references.pmid: 22741032
references.citation: Cancer Res. 2012 May 15;72(10):2600-8
references.pmid: 22589277
references.citation: J Biol Chem. 1997 Nov 14;272(46):29091-8
references.pmid: 9360984
references.citation: J Biol Chem. 2007 Jan 19;282(3):1788-96
references.pmid: 17060326
references.citation: ISRN Oncol. 2012;2012:137289
references.pmid: 23119185
references.citation: Cell Death Differ. 2003 Aug;10(8):864-9
references.pmid: 12867993
references.citation: Nitric Oxide. 2009 Feb;20(1):39-52
references.pmid: 18778787
references.citation: Transl Oncol. 2012 Apr;5(2):66-71
references.pmid: 22496921
references.citation: Toxicology. 2005 Mar 15;208(2):249-58
references.pmid: 15691589
references.citation: Curr Med Chem. 2003 May;10(10):845-55
references.pmid: 12678687
references.citation: J Immunol. 2001 Jul 1;167(1):75-81
references.pmid: 11418634
references.citation: Semin Cancer Biol. 2008 Apr;18(2):131-40
references.pmid: 18291670