AUB ScholarWorks

Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species

Show simple item record Fatfat M. Merhi R.A. Rahal O. Stoyanovsky D.A. Zaki A. Haidar H. Kagan V.E. Gali-Muhtasib H. Machaca K.
dc.contributor.editor 2014 2017-10-03T15:43:32Z 2017-10-03T15:43:32Z 2014
dc.identifier 10.1186/1471-2407-14-527
dc.identifier.issn 14712407
dc.description.abstract Background: Metals including iron, copper and zinc are essential for physiological processes yet can be toxic at high concentrations. However the role of these metals in the progression of cancer is not well defined. Here we study the anti-tumor activity of the metal chelator, TPEN, and define its mechanism of action.Methods: Multiple approaches were employed, including cell viability, cell cycle analysis, multiple measurements of apoptosis, and mitochondrial function. In addition we measured cellular metal contents and employed EPR to record redox cycling of TPEN-metal complexes. Mouse xenografts were also performed to test the efficacy of TPEN in vivo.Results: We show that metal chelation using TPEN (5μM) selectively induces cell death in HCT116 colon cancer cells without affecting the viability of non-cancerous colon or intestinal cells. Cell death was associated with increased levels of reactive oxygen species (ROS) and was inhibited by antioxidants and by prior chelation of copper. Interestingly, HCT116 cells accumulate copper to 7-folds higher levels than normal colon cells, and the TPEN-copper complex engages in redox cycling to generate hydroxyl radicals. Consistently, TPEN exhibits robust anti-tumor activity in vivo in colon cancer mouse xenografts.Conclusion: Our data show that TPEN induces cell death by chelating copper to produce TPEN-copper complexes that engage in redox cycling to selectively eliminate colon cancer cells. © 2014 Fatfat et al.; licensee BioMed Central Ltd.
dc.language English
dc.publisher BioMed Central Ltd.; LONDON
dc.relation.ispartof Publication Name: BMC Cancer; Publication Year: 2014; Volume: 14; no. 1;
dc.source Scopus
dc.title Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species
dc.type Article
dc.contributor.affiliation Fatfat, M., Department of Biology, American University of Beirut, Beirut, Lebanon
dc.contributor.affiliation Merhi, R.A., Department of Biology, Lebanese University, Beirut, Lebanon
dc.contributor.affiliation Rahal, O., Department of Biology, American University of Beirut, Beirut, Lebanon
dc.contributor.affiliation Stoyanovsky, D.A., Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, United States
dc.contributor.affiliation Zaki, A., Department of Biology, American University of Beirut, Beirut, Lebanon
dc.contributor.affiliation Haidar, H., Department of Biology, American University of Beirut, Beirut, Lebanon
dc.contributor.affiliation Kagan, V.E., Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, United States
dc.contributor.affiliation Gali-Muhtasib, H., Department of Biology, American University of Beirut, Beirut, Lebanon
dc.contributor.affiliation Machaca, K., Department of Physiology and Biophysics, Weill Cornell Medical College, Doha, Qatar
dc.contributor.authorAddress Gali-Muhtasib, H.; Department of Biology, American University of Beirut, Beirut, Lebanon; email:
dc.contributor.authorCorporate University: American University of Beirut; Faculty: Faculty of Arts and Sciences; Department: Biology;
dc.contributor.authorDepartment Biology
dc.contributor.faculty Faculty of Arts and Sciences
dc.contributor.authorInitials Fatfat, M
dc.contributor.authorInitials Abou Merhi, R
dc.contributor.authorInitials Rahal, O
dc.contributor.authorInitials Stoyanovsky, DA
dc.contributor.authorInitials Zaki, A
dc.contributor.authorInitials Haidar, H
dc.contributor.authorInitials Kagan, VE
dc.contributor.authorInitials Gali-Muhtasib, H
dc.contributor.authorInitials Machaca, K
dc.contributor.authorReprintAddress Gali-Muhtasib, H (reprint author), Amer Univ Beirut, Dept Biol, Beirut, Lebanon.
dc.contributor.authorUniversity American University of Beirut
dc.description.cited Adler M, 1997, TOXICON, V35, P1089, DOI 10.1016-S0041-0101(96)00215-2; Adler M, 1999, NEUROTOXICOLOGY, V20, P571; Armstrong C, 2001, BRAIN RES, V892, P51, DOI 10.1016-S0006-8993(00)03195-4; ARSLAN P, 1985, J BIOL CHEM, V260, P2719; Beyersmann D, 2001, BIOMETALS, V14, P331, DOI 10.1023-A:1012905406548; Boonstra J, 2004, GENE, V337, P1, DOI 10.1016-j.gene.2004.04.032; Carraway RE, 2012, BBA-MOL CELL RES, V1823, P544, DOI 10.1016-j.bbamcr.2011.09.013; Chai F, 2000, J INFECT DIS, V182, pS85, DOI 10.1086-315914; Dilda PJ, 2007, CANCER TREAT REV, V33, P542, DOI 10.1016-j.ctrv.2007.05.001; Ding WQ, 2008, CANCER LETT, V271, P251, DOI 10.1016-j.canlet.2008.06.011; Ding XQ, 2011, J NUTR BIOCHEM, V22, P301, DOI 10.1016-j.jnutbio.2010.06.010; Donadelli M, 2008, J CELL BIOCHEM, V104, P202, DOI 10.1002-jcb.21613; Finney LA, 2003, SCIENCE, V300, P931, DOI 10.1126-science.1085049; Gali-Muhtasib H, 2008, CANCER RES, V68, P5609, DOI 10.1158-0008-5472.CAN-08-0884; Gunay A, 2010, CHEM REV, V110, P1060, DOI 10.1021-cr900269x; Gupte A, 2009, CANCER TREAT REV, V35, P32, DOI 10.1016-j.ctrv.2008.07.004; Gurusamy KS, 2011, BIOMETALS, V24, P143, DOI 10.1007-s10534-010-9382-5; Hashemi M, 2007, EUR J PHARMACOL, V557, P9, DOI 10.1016-j.ejphar.2006.11.010; Hornle M, 2011, ONCOGENE, V30, P575, DOI 10.1038-onc.2010.434; Hyun HJ, 2001, INVEST OPHTH VIS SCI, V42, P460; Jungwirth U, 2011, ANTIOXID REDOX SIGN, V15, P1085, DOI 10.1089-ars.2010.3663; Kastan MB, 2004, NATURE, V432, P316, DOI 10.1038-nature03097; Kim AM, 2010, NAT CHEM BIOL, V6, P674, DOI [10.1038-nchembio.419, 10.1038-NCHEMBIO.419]; Kolenko VM, 2001, APOPTOSIS, V6, P419, DOI 10.1023-A:1012497926537; Lovejoy DB, 2011, CANCER RES, V71, P5871, DOI 10.1158-0008-5472.CAN-11-1218; Lyakin OY, 2011, INORG CHEM, V50, P5526, DOI 10.1021-ic200088e; Makhov P, 2008, CELL DEATH DIFFER, V15, P1745, DOI 10.1038-cdd.2008.106; MOHINDRU A, 1983, BIOCHEM PHARMACOL, V32, P3627, DOI 10.1016-0006-2952(83)90314-3; Nakatani T, 2000, CHEM-BIOL INTERACT, V125, P151, DOI 10.1016-S0009-2797(99)00166-0; Nam W, 2007, ACCOUNTS CHEM RES, V40, P522, DOI 10.1021-ar700027f; Perdiguero E, 2004, CELL CYCLE, V3, P733; Peters ZJ, 2007, REPROD TOXICOL, V23, P520; Richardson DR, 2006, J MED CHEM, V49, P6510, DOI 10.1021-jm0606342; Sun L, 2007, J CELL PHYSIOL, V213, P98, DOI 10.1002-jcp.21090; Trachootham D, 2009, NAT REV DRUG DISCOV, V8, P579, DOI 10.1038-nrd2803; Trinder D, 1996, HEPATOLOGY, V23, P1512, DOI 10.1002-hep.510230631; Vermeulen K, 2003, CELL PROLIFERAT, V36, P131, DOI 10.1046-j.1365-2184.2003.00266.x; Whitnall M, 2006, P NATL ACAD SCI USA, V103, P14901, DOI 10.1073-pnas.0604979103; ZALEWSKI PD, 1993, BIOCHEM J, V296, P403; Zubair H, 2013, CELL DEATH DIS, V4, DOI 10.1038-cddis.2013.172
dc.description.citedTotWOSCount 0
dc.description.citedWOSCount 0
dc.format.extentCount 1
dc.identifier.articleNo 527
dc.identifier.coden BCMAC
dc.identifier.scopusID 84904446830
dc.publisher.address 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
dc.relation.ispartOfISOAbbr BMC Cancer
dc.relation.ispartOfIssue 1
dc.relation.ispartofPubTitle BMC Cancer
dc.relation.ispartofPubTitleAbbr BMC Cancer
dc.relation.ispartOfVolume 14
dc.source.ID WOS:000339970800006
dc.type.publication Journal
dc.subject.otherAuthKeyword Colon cancer
dc.subject.otherAuthKeyword Copper
dc.subject.otherAuthKeyword Metal chelation
dc.subject.otherAuthKeyword Reactive oxygen species
dc.subject.otherAuthKeyword Redox cycling
dc.subject.otherAuthKeyword TPEN
dc.subject.otherChemCAS copper, 15158-11-9, 7440-50-8
dc.subject.otherChemCAS hydroxyl radical, 3352-57-6
dc.subject.otherChemCAS n,n,n',n' tetrakis(2 pyridylmethyl)ethylenediamine, 16858-02-9
dc.subject.otherChemCAS zinc, 7440-66-6, 14378-32-6
dc.subject.otherIndex antioxidant
dc.subject.otherIndex copper
dc.subject.otherIndex hydroxyl radical
dc.subject.otherIndex n,n,n',n' tetrakis(2 pyridylmethyl)ethylenediamine
dc.subject.otherIndex reactive oxygen metabolite
dc.subject.otherIndex zinc
dc.subject.otherIndex animal experiment
dc.subject.otherIndex animal model
dc.subject.otherIndex animal tissue
dc.subject.otherIndex apoptosis
dc.subject.otherIndex article
dc.subject.otherIndex cancer inhibition
dc.subject.otherIndex cell viability
dc.subject.otherIndex chelation
dc.subject.otherIndex colon cancer
dc.subject.otherIndex controlled study
dc.subject.otherIndex drug cytotoxicity
dc.subject.otherIndex drug efficacy
dc.subject.otherIndex drug selectivity
dc.subject.otherIndex female
dc.subject.otherIndex HCT116 cell line
dc.subject.otherIndex human
dc.subject.otherIndex human cell
dc.subject.otherIndex in vivo study
dc.subject.otherIndex intestine cell
dc.subject.otherIndex mouse
dc.subject.otherIndex nonhuman
dc.subject.otherIndex oxidation reduction reaction
dc.subject.otherIndex tumor xenograft
dc.subject.otherKeywordPlus INTRACELLULAR ZINC
dc.subject.otherKeywordPlus ANTITUMOR-ACTIVITY
dc.subject.otherKeywordPlus INDUCED APOPTOSIS
dc.subject.otherKeywordPlus MAMMALIAN-CELLS
dc.subject.otherKeywordPlus DEPLETION
dc.subject.otherKeywordPlus TPEN
dc.subject.otherKeywordPlus POTENT
dc.subject.otherKeywordPlus TRANSITION
dc.subject.otherKeywordPlus COMPLEXES
dc.subject.otherKeywordPlus MECHANISM
dc.subject.otherWOS Oncology

Files in this item

Files Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record

Search AUB ScholarWorks


My Account