title: Role of nitric oxide in the chemistry and anticancer activity of etoposide (VP-16,213).
abstract: Originally identified as an innate cytotoxin, nitric oxide ((·)NO) formation in tumors can influence chemotherapy and exacerbate cancer progression. Here, we examined the hypothesis that (·)NO generation contributes to cancer cell drug resistance toward the widely used anticancer drug Etoposide (VP-16). The UV-vis spectrum of VP-16 was not changed by exposure of VP-16 to (·)NO in aqueous buffer. In contrast, reddish-orange compound(s) characteristic of o-quinone- and nitroso-VP-16 were readily generated in a hydrophobic medium (chloroform) in an oxygen-dependent manner. Similar products were also formed when the VP-16 radical, generated from VP-16 and horseradish peroxidase/H2O2, was exposed directly to (·)NO in chloroform in the presence of oxygen. Separation and spectral analysis of VP-16 reaction extracts by electron spin resonance and UV-vis indicated the generation of the phenoxy radical and the o-quinone of VP-16, as well as putative nitroxide, iminoxyl, and other nitrogen oxide intermediates. Nitric oxide products of VP-16 displayed significantly diminished topoisomerase II-dependent cleavage of DNA and cytotoxicity to human HL-60 leukemia cells. LPS-mediated induction of nitric oxide synthase in murine macrophages resulted in VP-16 resistance compared to Raw cells. Furthermore, (·)NO products derived from iNOS rapidly reacted with VP-16 leading to decreased DNA damage and cytotoxicity. Together, these observations suggest that the formation of (·)NO in tumors (associated macrophages) can contribute to VP-16 resistance via the detoxification of VP-16.
authors: Laboratory of Toxicology & Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, United States.
authors: Birandra K
authors: BK
authors: Sinha
authors: Suchandra
authors: S
authors: Bhattacharjee
authors: Saurabh
authors: S
authors: Chatterjee
authors: JinJie
authors: J
authors: Jiang
authors: Ann G
authors: AG
authors: Motten
authors: Ashutosh
authors: A
authors: Kumar
authors: Michael Graham
authors: MG
authors: Espey
authors: Ronald P
authors: RP
authors: Mason
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D004578:Electron Spin Resonance Spectroscopy; D005047:Etoposide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000970:Antineoplastic Agents; D009569:Nitric Oxide; D005047:Etoposide
references: Biochem Pharmacol. 1985 Dec 15;34(24):4191-5
references: 3000380
references: Mol Pharmacol. 1999 Sep;56(3):494-506
references: 10462537
references: Cell Cycle. 2011 Feb 15;10(4):619-24
references: 21293193
references: J Leukoc Biol. 2008 Sep;84(3):623-30
references: 18467655
references: J Biol Chem. 1994 Aug 26;269(34):21891-7
references: 7520445
references: Cancer Res. 1988 Sep 15;48(18):5096-100
references: 2842045
references: Chem Res Toxicol. 2006 Jul;19(7):937-43
references: 16841962
references: J Clin Invest. 2010 Nov;120(11):3843-54
references: 20978357
references: J Biol Chem. 2000 Apr 14;275(15):11341-7
references: 10753947
references: Nitric Oxide. 2000 Apr;4(2):147-56
references: 10835295
references: Cancer Res. 2006 Jul 1;66(13):6459-62
references: 16818612
references: Drugs. 1990 Mar;39(3):438-90
references: 2184009
references: Cancer Res. 1997 Aug 1;57(15):3300-4
references: 9242464
references: Nitric Oxide. 2008 Sep;19(2):133-7
references: 18472017
references: Cancer Res. 1987 Nov 15;47(22):5835-40
references: 3117357
references: Cancer. 2008 Jan 15;112(2):372-81
references: 18008356
references: J Biol Chem. 2001 Aug 10;276(32):30085-91
references: 11404354
references: Am J Physiol Cell Physiol. 2009 May;296(5):C1133-9
references: 19279235
references: J Biol Chem. 2008 Jul 4;283(27):18513-21
references: 18445594
references: Eur J Cancer. 1990;26(5):590-3
references: 2169277
references: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2175-9
references: 9482858
references: Mol Pharmacol. 1998 Mar;53(3):422-8
references: 9495807
references: Curr Pharm Des. 2010;16(4):381-91
references: 20236067
references: FEBS Lett. 1988 Jan 25;227(2):240-4
references: 2828121
references: Cancer Res. 2001 Nov 1;61(21):7777-84
references: 11691792
references: Chem Res Toxicol. 2007 Apr;20(4):709-14
references: 17388608
references: J Magn Reson B. 1994 Jun;104(2):105-10
references: 8049862
references: Nitric Oxide. 1997 Feb;1(1):88-94
references: 9701048
references: Antimicrob Agents Chemother. 1989 Oct;33(10):1697-703
references: 2556075
references: Cell Res. 2002 Dec;12(5-6):311-20
references: 12528889
references: J Pharmacol Exp Ther. 2007 Feb;320(2):782-9
references: 17108235
references: Cancer Res. 1988 Feb 1;48(3):589-601
references: 3335022
references: Arch Biochem Biophys. 1996 Nov 15;335(2):369-76
references: 8914934
references: Biochem Biophys Res Commun. 1996 Jul 25;224(3):696-702
references: 8713109
references: Med Pediatr Oncol. 2001 May;36(5):525-35
references: 11340607
references: Biochemistry. 1976 Dec 14;15(25):5443-8
references: 999819
references: Cancer Res. 2006 Jan 15;66(2):605-12
references: 16423985
references: Biochem Pharmacol. 1987 Feb 15;36(4):527-36
references: 3030329
references: Prostate. 1993;23(1):25-36
references: 8393191
references: Biochemistry. 2001 Feb 6;40(5):1159-70
references: 11170441
references: Biochemistry. 1989 May 30;28(11):4839-46
references: 2548593
references: J Biol Chem. 1983 Dec 25;258(24):15365-70
references: 6317692
references: Biochemistry. 1984 Mar 13;23(6):1183-8
references: 6712942
references: Br J Cancer. 1997;76(3):325-34
references: 9252199
references: Free Radic Res. 1999 Dec;31(6):597-606
references: 10630683
references: PLoS One. 2009 Aug 21;4(8):e6713
references: 19696929
references: Biochemistry (Mosc). 1998 Jul;63(7):802-9
references: 9721332
references: Chem Biol Interact. 1987;62(3):237-47
references: 3040275
references: Biochem Biophys Res Commun. 1986 Feb 26;135(1):215-20
references: 3006680
references: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4392-6
references: 7538668
references: Cancer Res. 1986 Apr;46(4 Pt 2):1934-8
references: 3004711
references: Cancer Res. 2002 Apr 15;62(8):2227-31
references: 11956073
references: Biochim Biophys Acta. 1990 Nov 14;1096(1):81-3
references: 2176549
references: Cancer Res. 1987 Sep 1;47(17):4658-62
references: 3621161
references: Toxicology. 2002 Aug 1;177(1):1-9
references: 12126791
references: J Immunol. 2009 Sep 15;183(6):4055-66
references: 19717511
references: J Biol Chem. 1977 Jan 25;252(2):536-41
references: 188819
references: J Biol Chem. 1997 Feb 21;272(8):4959-63
references: 9030556
references: Ann N Y Acad Sci. 2002 May;962:8-17
references: 12076959