title: Mitochondria and redox homoeostasis as chemotherapeutic targets.
abstract: Characteristics of cancer cells include a more oxidized redox environment, metabolic reprogramming and apoptosis resistance. Our studies with a lymphoma model have explored connections between the cellular redox environment and cancer cell phenotypes. Alterations seen in lymphoma cells made resistant to oxidative stress include: a more oxidized redox environment despite increased expression of antioxidant enzymes, enhanced net tumour growth, metabolic changes involving the mitochondria and resistance to the mitochondrial pathway to apoptosis. Of particular importance, the cells show cross-resistance to multiple chemotherapeutic agents used to treat aggressive lymphomas. Analyses of clinical and tumour data reveal the worst prognosis when patients' lymphomas have gene expression patterns consistent with the most oxidized redox environment. Lymphomas from patients with the worst survival outcomes express increased levels of proteins involved in oxidative phosphorylation, including cytochrome c. This is consistent with these cells functioning as metabolic opportunists. Using lymphoma cell models and primary lymphoma cultures, we observed enhanced killing using genetic and drug approaches which further oxidize the cellular redox environment. These approaches include increased expression of SOD2 (superoxide dismutase 2), treatment with a manganoporphyrin that oxidizes the glutathione redox couple, or treatment with a copper chelator that inhibits SOD1 and leads to peroxynitrite-dependent cell death. The latter approach effectively kills lymphoma cells that overexpress the anti-apoptotic protein Bcl-2. Given the central role of mitochondria in redox homoeostasis, metabolism and the intrinsic pathway to apoptosis, our studies support the development of new anti-cancer drugs to target this organelle.
authors.affiliation: *Department of Pathology, University of Arizona, P.O. Box 24-5043, Tucson, AZ 85724-5043, U.S.A.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Briehl
authors.affiliation: †Department of Medical Pharmacology, University of Arizona, P.O. Box 24-5050, Tucson, AZ 85724-5050, U.S.A.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Tome
authors.affiliation: ‡Cancer Biology Graduate Interdisciplinary Program, University of Arizona, P.O. Box 24-5024, Tucson, AZ 85724-5024, U.S.A.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Wilkinson
authors.affiliation: ‡Cancer Biology Graduate Interdisciplinary Program, University of Arizona, P.O. Box 24-5024, Tucson, AZ 85724-5024, U.S.A.
authors.forename: Melba C
authors.initials: MC
authors.lastname: Jaramillo
authors.affiliation: ‡Cancer Biology Graduate Interdisciplinary Program, University of Arizona, P.O. Box 24-5024, Tucson, AZ 85724-5024, U.S.A.
authors.forename: Kristy
authors.initials: K
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008223:Lymphoma / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents
references.citation: Free Radic Biol Med. 2001 Jun 1;30(11):1191-212
references.pmid: 11368918
references.citation: Free Radic Biol Med. 2013 Jul;60:157-67
references.pmid: 23416365
references.citation: Exp Hematol Oncol. 2012 Mar 26;1(1):2
references.pmid: 23210982
references.citation: J Biol Chem. 2007 Jun 22;282(25):18427-18436
references.pmid: 17468103
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
references.pmid: 18032601
references.citation: Curr Opin Investig Drugs. 2007 Dec;8(12):1022-37
references.pmid: 18058573
references.citation: J Exp Med. 2001 Dec 17;194(12):1861-74
references.pmid: 11748286
references.citation: Nature. 2003 Aug 21;424(6951):952-6
references.pmid: 12931191
references.citation: Free Radic Biol Med. 2012 Apr 15;52(8):1272-84
references.pmid: 22330065
references.citation: Blood. 1992 Aug 15;80(4):879-86
references.pmid: 1498330
references.citation: Biochim Biophys Acta. 2004 Jul 23;1693(1):57-72
references.pmid: 15276325
references.citation: Mol Cell. 2004 Dec 3;16(5):819-30
references.pmid: 15574336
references.citation: Drugs. 2011 Jul 30;71(11):1385-96
references.pmid: 21812504
references.citation: Cell Death Differ. 2001 Sep;8(9):953-61
references.pmid: 11526450
references.citation: Nat Rev Mol Cell Biol. 2014 Jan;15(1):49-63
references.pmid: 24355989
references.citation: Nature. 2000 Feb 3;403(6769):503-11
references.pmid: 10676951
references.citation: N Engl J Med. 2002 Jun 20;346(25):1937-47
references.pmid: 12075054
references.citation: Mitochondrion. 2013 May;13(3):170-88
references.pmid: 22820117
references.citation: Exp Ther Med. 2012 May;3(5):845-852
references.pmid: 22529877
references.citation: Blood. 2005 Mar 1;105(5):1851-61
references.pmid: 15550490
references.citation: Free Radic Biol Med. 2011 Sep 1;51(5):1035-53
references.pmid: 21616142
references.citation: Carcinogenesis. 2010 Jan;31(1):37-49
references.pmid: 19955394
references.citation: Cell. 2009 Mar 6;136(5):823-37
references.pmid: 19269363
references.citation: Drug Resist Updat. 2004 Apr;7(2):97-110
references.pmid: 15158766
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Int J Mol Sci. 2012;13(8):10212-28
references.pmid: 22949856
references.citation: Biochem Soc Trans. 2003 Dec;31(Pt 6):1441-4
references.pmid: 14641084
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
references.pmid: 19033189
references.citation: Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):508-14
references.pmid: 15706098
references.citation: Antioxid Redox Signal. 2011 Dec 15;15(12):2975-87
references.pmid: 21574773
references.citation: Free Radic Biol Med. 1999 Dec;27(11-12):1208-18
references.pmid: 10641713
references.citation: Cancer Res. 2009 Mar 15;69(6):2163-6
references.pmid: 19258498
references.citation: Biochem J. 2007 Jan 1;401(1):1-11
references.pmid: 17150040
references.citation: Curr Opin Chem Biol. 2011 Feb;15(1):156-61
references.pmid: 21075043
references.citation: Blood. 2005 Nov 15;106(10):3594-601
references.pmid: 16081686
references.citation: J Biol Chem. 1998 Sep 18;273(38):24521-8
references.pmid: 9733746
references.citation: Oncol Lett. 2010 Mar;1(2):227-230
references.pmid: 20798784
references.citation: Genes Dev. 2001 Jun 1;15(11):1406-18
references.pmid: 11390360
references.citation: Clin Cancer Res. 2006 Aug 15;12(16):4974-82
references.pmid: 16914587
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2069-77
references.pmid: 17119030
references.citation: Cancer Res. 2001 Mar 15;61(6):2766-73
references.pmid: 11289160
references.citation: Cancer Cell. 2012 Oct 16;22(4):547-60
references.pmid: 23079663
references.citation: J Biol Chem. 2001 Oct 19;276(42):38388-93
references.pmid: 11507097
references.citation: Blood. 2007 Apr 15;109(8):3409-16
references.pmid: 17179223
references.citation: Cancer Res. 2009 Jul 1;69(13):5450-7
references.pmid: 19549914