title: Ascorbate/menadione-induced oxidative stress kills cancer cells that express normal or mutated forms of the oncogenic protein Bcr-Abl. An in vitro and in vivo mechanistic study.
abstract: Numerous studies suggest that generation of oxidative stress could be useful in cancer treatment. In this study, we evaluated, in vitro and in vivo, the antitumor potential of oxidative stress induced by ascorbate/menadione (asc/men). This combination of a reducing agent (ascorbate) and a redox active quinone (menadione) generates redox cycling leading to formation of reactive oxygen species (ROS). Asc/men was tested in several cell types including K562 cells (a stable human-derived leukemia cell line), freshly isolated leukocytes from patients with chronic myeloid leukemia, BaF3 cells (a murine pro-B cell line) transfected with Bcr-Abl and peripheral blood leukocytes derived from healthy donors. Although these latter cells were resistant to asc/men, survival of all the other cell lines was markedly reduced, including the BaF3 cells expressing either wild-type or mutated Bcr-Abl. In a standard in vivo model of subcutaneous tumor transplantation, asc/men provoked a significant delay in the proliferation of K562 and BaF3 cells expressing the T315I mutated form of Bcr-Abl. No effect of asc/men was observed when these latter cells were injected into blood of mice most probably because of the high antioxidant potential of red blood cells, as shown by in vitro experiments. We postulate that cancer cells are more sensitive to asc/men than healthy cells because of their lack of antioxidant enzymes, mainly catalase. The mechanism underlying this cytotoxicity involves the oxidative cleavage of Hsp90 with a subsequent loss of its chaperone function thus leading to degradation of wild-type and mutated Bcr-Abl protein.
authors.affiliation: Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, avenue E. Mounier 73, 1200 Bruxelles, Belgium.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Beck
authors.forename: Rozangela Curi
authors.initials: RC
authors.lastname: Pedrosa
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dejeans
authors.forename: Christophe
authors.initials: C
authors.lastname: Glorieux
authors.forename: Philippe
authors.initials: P
authors.lastname: Levêque
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
authors.forename: Henryk
authors.initials: H
authors.lastname: Taper
authors.forename: Stéphane
authors.initials: S
authors.lastname: Eeckhoudt
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.forename: Pedro Buc
authors.initials: PB
authors.lastname: Calderon
authors.forename: Julien
authors.initials: J
authors.lastname: Verrax
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D024483:Vitamin K 3 / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D050505:Mutant Proteins; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D016044:Fusion Proteins, bcr-abl; D001205:Ascorbic Acid
references.citation: Science. 1990 Mar 2;247(4946):1079-82
references.pmid: 2408149
references.citation: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6649-53
references.pmid: 2204061
references.citation: Int J Toxicol. 2009 Jan-Feb;28(1):33-42
references.pmid: 19482829
references.citation: Biochem Pharmacol. 2010 May 1;79(9):1221-30
references.pmid: 20006589
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9
references.pmid: 16157892
references.citation: Cancer Cell. 2002 Aug;2(2):117-25
references.pmid: 12204532
references.citation: Blood. 1995 Nov 15;86(10):3897-904
references.pmid: 7579359
references.citation: J Clin Invest. 1986 Jan;77(1):319-21
references.pmid: 3944256
references.citation: Blood. 2001 Mar 1;97(5):1404-12
references.pmid: 11222387
references.citation: J Natl Cancer Inst. 2007 May 2;99(9):680-93
references.pmid: 17470736
references.citation: Biochem J. 1964 Jul;92(1):179-84
references.pmid: 4378796
references.citation: Cancer Cell. 2006 Sep;10(3):241-52
references.pmid: 16959615
references.citation: J Clin Invest. 1987 Nov;80(5):1486-91
references.pmid: 2824562
references.citation: Blood. 1996 Aug 1;88(3):1052-61
references.pmid: 8704214
references.citation: Apoptosis. 2004 Mar;9(2):223-33
references.pmid: 15004519
references.citation: Int J Cancer. 1989 Dec 15;44(6):1028-33
references.pmid: 2558077
references.citation: Cell Growth Differ. 2000 Jul;11(7):355-60
references.pmid: 10939589
references.citation: Antioxid Redox Signal. 2009 Dec;11(12):3013-69
references.pmid: 19496700
references.citation: Science. 1990 Feb 16;247(4944):824-30
references.pmid: 2406902
references.citation: Eur J Med Chem. 2003 May;38(5):451-7
references.pmid: 12767595
references.citation: Blood. 2003 Dec 15;102(13):4512-9
references.pmid: 12920036
references.citation: Nat Rev Drug Discov. 2009 Jul;8(7):579-91
references.pmid: 19478820
references.citation: Free Radic Res. 2005 Jun;39(6):649-57
references.pmid: 16036343
references.citation: Cancer Metastasis Rev. 2006 Dec;25(4):695-705
references.pmid: 17160708
references.citation: EMBO J. 1990 Apr;9(4):1069-78
references.pmid: 1691092
references.citation: Biochem Pharmacol. 2009 Feb 1;77(3):375-83
references.pmid: 19014912
references.citation: Biochem Soc Trans. 2003 Dec;31(Pt 6):1441-4
references.pmid: 14641084
references.citation: Int J Cancer. 2007 Mar 15;120(6):1192-7
references.pmid: 17163414
references.citation: Nature. 1990 Mar 15;344(6263):251-3
references.pmid: 2179728
references.citation: Biochem Pharmacol. 2006 Sep 14;72(6):671-80
references.pmid: 16828058
references.citation: Curr Med Chem. 2009;16(15):1821-30
references.pmid: 19442148
references.citation: Nat Med. 1996 May;2(5):561-6
references.pmid: 8616716
references.citation: J Clin Invest. 1984 Jul;74(1):292-5
references.pmid: 6330176