title: Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study.
abstract: In vitro studies have shown that hydrogen peroxide (H2O2) produced by high-concentration ascorbate and cell culture medium iron efficiently kills cancer cells. This provided the rationale for clinical trials of high-dose intravenous ascorbate-based treatment for cancer. A drawback in all the in vitro studies was their failure to take into account the in vivo concentration of iron to supplement cell culture media which are characterized by low iron content. Here we showed, using two prostate cancer cell lines (LNCaP and PC-3) and primary astrocytes, that the anticancer/cytotoxic effects of ascorbate are completely abolished by iron at physiological concentrations in cell culture medium and human plasma. A detailed examination of mechanisms showed that iron at physiological concentrations promotes both production and decomposition of H2O2. The latter is mediated by Fenton reaction and prevents H2O2 accumulation. The hydroxyl radical, which is produced in the Fenton reaction, is buffered by extracellular proteins, and could not affect intracellular targets like H2O2. These findings show that anticancer effects of ascorbate have been significantly overestimated in previous in vitro studies, and that common cell culture media might be unsuitable for redox research.
authors.affiliation: Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Despot Stefan Blvd. 142, 11060 Belgrade, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Mojić
authors.affiliation: Department of Life Sciences, Institute for Multidisciplinary Research, University of Belgrade, Kneza Višeslava 1, 11030 Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Bogdanović Pristov
authors.affiliation: Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Despot Stefan Blvd. 142, 11060 Belgrade, Serbia.
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimović-Ivanić
authors.affiliation: Inositide Laboratory, Cancer Research UK Manchester Institute, University of Manchester, Manchester, M20 4BX, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Department of Life Sciences, Institute for Multidisciplinary Research, University of Belgrade, Kneza Višeslava 1, 11030 Belgrade, Serbia.
authors.forename: Marina
authors.initials: M
authors.lastname: Stanić
authors.affiliation: Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Despot Stefan Blvd. 142, 11060 Belgrade, Serbia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatović
authors.affiliation: Department of Life Sciences, Institute for Multidisciplinary Research, University of Belgrade, Kneza Višeslava 1, 11030 Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojević
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D007501:Iron / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010084:Oxidation-Reduction; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D007501:Iron; D001205:Ascorbic Acid
references.citation: Nat Commun. 2014;5:3295
references.pmid: 24548894
references.citation: Methods Enzymol. 1990;186:464-78
references.pmid: 1978225
references.citation: Biotechniques. 2007 Nov;43(5):627-8, 630, 632 passim
references.pmid: 18072592
references.citation: Arch Biochem Biophys. 1996 Jun 15;330(2):401-8
references.pmid: 8660671
references.citation: Clin Sci (Lond). 2004 May;106(5):475-84
references.pmid: 14670072
references.citation: Annu Rev Med. 2011;62:347-60
references.pmid: 20887198
references.citation: J Invest Dermatol. 1972 Feb;58(2):96-8
references.pmid: 5060302
references.citation: J Clin Biochem Nutr. 2009 Nov;45(3):355-60
references.pmid: 19902028
references.citation: Breast Cancer Res Treat. 2012 Jun;133(3):881-8
references.pmid: 22048816
references.citation: Arch Biochem Biophys. 1959 May;82(1):70-7
references.pmid: 13650640
references.citation: Biochim Biophys Acta. 2012 Dec;1826(2):443-57
references.pmid: 22728050
references.citation: Cancer Res. 2003 Apr 15;63(8):1764-8
references.pmid: 12702559
references.citation: BMC Med Genomics. 2009 Jan 08;2:2
references.pmid: 19133145
references.citation: J Cell Physiol. 2005 Jul;204(1):192-7
references.pmid: 15672419
references.citation: Cancer Res. 2013 Aug 15;73(16):5232-41
references.pmid: 23764544
references.citation: Anal Biochem. 2004 Aug 15;331(2):370-5
references.pmid: 15265744
references.citation: Oxid Med Cell Longev. 2012;2012:596019
references.pmid: 23326624
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9
references.pmid: 16157892
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Ann Oncol. 2008 Nov;19(11):1969-74
references.pmid: 18544557
references.citation: Comp Biochem Physiol A Physiol. 1997 Sep;118(1):165-9
references.pmid: 9243818
references.citation: Fibrogenesis Tissue Repair. 2010 Jul 23;3:12
references.pmid: 20653943
references.citation: Free Radic Biol Med. 2014 Apr;69:308-17
references.pmid: 24495550
references.citation: Nat Chem Biol. 2014 Jan;10(1):9-17
references.pmid: 24346035
references.citation: Cancer Biother Radiopharm. 2010 Aug;25(4):439-48
references.pmid: 20735206
references.citation: Anal Biochem. 1979 Jun;95(2):351-8
references.pmid: 36810
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3704-9
references.pmid: 8623000
references.citation: J Clin Invest. 1995 Oct;96(4):1958-66
references.pmid: 7560088
references.citation: PLoS One. 2013 Oct 04;8(10):e76383
references.pmid: 24124554
references.citation: Arch Biochem Biophys. 1990 Jul;280(1):1-8
references.pmid: 2191627
references.citation: J Cell Biol. 1980 Jun;85(3):890-902
references.pmid: 6248568
references.citation: FEBS Lett. 2003 Apr 10;540(1-3):3-6
references.pmid: 12681474
references.citation: PLoS One. 2013 Apr 23;8(4):e62717
references.pmid: 23626851
references.citation: Cancer Chemother Pharmacol. 2013 Mar;71(3):765-75
references.pmid: 23381814
references.citation: Redox Rep. 2010;15(1):29-35
references.pmid: 20196926
references.citation: Free Radic Biol Med. 1993 Jun;14(6):649-53
references.pmid: 8392021
references.citation: Asia Pac J Clin Oncol. 2014 Mar;10(1):22-37
references.pmid: 24571058
references.citation: J Cell Mol Med. 2014 Mar;18(3):530-41
references.pmid: 24330097
references.citation: Sci Rep. 2013 Oct 30;3:3081
references.pmid: 24170119
references.citation: J Biomol Screen. 2006 Dec;11(8):922-32
references.pmid: 16973921
references.citation: Antioxid Redox Signal. 2001 Feb;3(1):157-63
references.pmid: 11291594
references.citation: Int J Biochem Cell Biol. 2004 Nov;36(11):2180-95
references.pmid: 15313465
references.citation: Clin Chim Acta. 1968 Jul;21(1):159-60
references.pmid: 5658949
references.citation: Free Radic Res. 2013 Mar;47(3):154-63
references.pmid: 23205739
references.citation: Antioxid Redox Signal. 2013 Dec 10;19(17):2141-56
references.pmid: 23621620
references.citation: Proc Natl Acad Sci U S A. 2007 May 22;104(21):8749-54
references.pmid: 17502596
references.citation: Crit Rev Clin Lab Sci. 2011 May-Jun;48(3):114-42
references.pmid: 21875311
references.citation: J Biol Chem. 2005 Dec 23;280(51):41928-39
references.pmid: 16223732
references.citation: Cancer Chemother Pharmacol. 2013 Jul;72(1):139-46
references.pmid: 23670640
references.citation: Mol Cancer. 2007 Aug 30;6:55
references.pmid: 17760959
references.citation: Anticancer Res. 2007 Sep-Oct;27(5A):3059-65
references.pmid: 17970045
references.citation: Free Radic Biol Med. 2011 Jun 15;50(12):1726-7
references.pmid: 21459141
references.citation: J Neurosci Res. 2010 Feb 15;88(3):563-71
references.pmid: 19746426
references.citation: Mol Cell Biol. 2008 Aug;28(16):5106-19
references.pmid: 18559422
references.citation: Free Radic Biol Med. 2012 Apr 15;52(8):1486-93
references.pmid: 22342518
references.citation: Cell Physiol Biochem. 2010;25(6):767-74
references.pmid: 20511723
references.citation: Am J Respir Crit Care Med. 1999 Jan;159(1):100-6
references.pmid: 9872825
references.citation: P R Health Sci J. 2005 Dec;24(4):269-76
references.pmid: 16570523
references.citation: N Engl J Med. 1985 Jan 17;312(3):178-9
references.pmid: 3965937