Bioflavonoids cause DNA double-strand breaks and chromosomal translocations through topoisomerase II-dependent and -independent mechanisms.
Animals
Cell Line
Chromosome Breakpoints
/ drug effects
Chromosomes, Mammalian
/ drug effects
DNA
/ chemistry
DNA Breaks, Double-Stranded
/ drug effects
DNA Repair
/ drug effects
DNA Topoisomerases, Type II
/ genetics
Dexrazoxane
/ pharmacology
Etoposide
/ toxicity
Flavonoids
/ toxicity
Genistein
/ toxicity
Histones
/ genetics
Kaempferols
/ toxicity
Luteolin
/ toxicity
Mice
Mouse Embryonic Stem Cells
/ drug effects
Quercetin
/ toxicity
Topoisomerase II Inhibitors
/ pharmacology
Translocation, Genetic
/ drug effects
DNA damage
Double-strand break
Environmental mutagenesis
Etoposide
Genome instability
Topoisomerase II
Journal
Mutation research. Genetic toxicology and environmental mutagenesis
ISSN: 1879-3592
Titre abrégé: Mutat Res Genet Toxicol Environ Mutagen
Pays: Netherlands
ID NLM: 101632149
Informations de publication
Date de publication:
Jan 2020
Jan 2020
Historique:
received:
18
11
2019
revised:
16
01
2020
accepted:
17
01
2020
entrez:
24
2
2020
pubmed:
24
2
2020
medline:
23
4
2020
Statut:
ppublish
Résumé
Bioflavonoids have a similar chemical structure to etoposide, the well-characterized topoisomerase II (Top2) poison, and evidence shows that they also induce DNA double-strand breaks (DSBs) and promote genome rearrangements. The purpose of this study was to determine the kinetics of bioflavonoid-induced DSB appearance and repair, and their dependence on Top2. Cells were exposed to bioflavonoids individually or in combination in the presence or absence of the Top2 catalytic inhibitor dexrazoxane. The kinetics of appearance and repair of γH2AX foci were measured. In addition, the frequency of resultant MLL-AF9 breakpoint cluster region translocations was determined. Bioflavonoids readily induced the appearance of γH2AX foci, but bioflavonoid combinations did not act additively or synergistically to promote DSBs. Myricetin-induced DSBs were mostly reduced by dexrazoxane, while genistein and quercetin-induced DSBs were only partially, but significantly, reduced. By contrast, luteolin and kaempferol-induced DSBs increased with dexrazoxane pre-treatment. Sensitivity to Top2 inhibition correlated with a significant reduction of bioflavonoid-induced MLL-AF9 translocations. These data demonstrate that myricetin, genistein, and quercetin act most similar to etoposide although with varying Top2-dependence. By contrast, luteolin and kaempferol have distinct kinetics that are mostly Top2-independent. These findings have implications for understanding the mechanisms of bioflavonoid activity and the potential of individual bioflavonoids to promote chromosomal translocations. Further, they provide direct evidence that specific Top2 inhibitors or targeted drugs could be developed that possess less leukemic potential or suppress chromosomal translocations associated with therapy-related and infant leukemias.
Identifiants
pubmed: 32087851
pii: S1383-5718(20)30014-0
doi: 10.1016/j.mrgentox.2020.503144
pmc: PMC7079294
mid: NIHMS1556390
pii:
doi:
Substances chimiques
Flavonoids
0
Histones
0
Kaempferols
0
Topoisomerase II Inhibitors
0
gamma-H2AX protein, mouse
0
Dexrazoxane
048L81261F
Etoposide
6PLQ3CP4P3
kaempferol
731P2LE49E
myricetin
76XC01FTOJ
DNA
9007-49-2
Quercetin
9IKM0I5T1E
Genistein
DH2M523P0H
DNA Topoisomerases, Type II
EC 5.99.1.3
Luteolin
KUX1ZNC9J2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
503144Subventions
Organisme : NCI NIH HHS
ID : R01 CA100159
Pays : United States
Organisme : NIGMS NIH HHS
ID : R15 GM120715
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM128571
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare no conflicts of interest.
Références
Antioxidants (Basel). 2019 Mar 25;8(3):
pubmed: 30934586
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4790-5
pubmed: 10758153
Crit Rev Food Sci Nutr. 2017 Aug 13;57(12):2589-2599
pubmed: 26357880
Biochim Biophys Acta. 1996 Jun 7;1307(2):239-47
pubmed: 8679710
Biochemistry. 2014 May 20;53(19):3229-36
pubmed: 24766193
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13950-4
pubmed: 9391133
Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):651-5
pubmed: 15767345
Leukemia. 2005 Dec;19(12):2289-95
pubmed: 16193084
Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8989-94
pubmed: 22615413
Cancer Res. 2007 Sep 15;67(18):8839-46
pubmed: 17875725
Nat Genet. 2010 Aug;42(8):668-75
pubmed: 20601956
Environ Res. 2005 Oct;99(2):195-203
pubmed: 16194669
Chromosoma. 2018 Jun;127(2):187-214
pubmed: 29327130
DNA Repair (Amst). 2006 Sep 8;5(9-10):1093-108
pubmed: 16857431
Annu Rev Nutr. 2002;22:19-34
pubmed: 12055336
Free Radic Biol Med. 2004 Aug 1;37(3):287-303
pubmed: 15223063
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):E934-43
pubmed: 22474351
J Tradit Complement Med. 2013 Jan;3(1):69-79
pubmed: 24716158
Mol Cell. 2019 Jul 25;75(2):252-266.e8
pubmed: 31202577
J Embryol Exp Morphol. 1985 Jun;87:27-45
pubmed: 3897439
Carcinogenesis. 2007 Aug;28(8):1703-9
pubmed: 17468513
Eur J Clin Nutr. 2007 Feb;61(2):248-54
pubmed: 16943849
Nat Struct Mol Biol. 2011 Jan;18(1):80-4
pubmed: 21131978
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10629-34
pubmed: 12963818
Nucleic Acids Res. 2009 Feb;37(3):738-48
pubmed: 19042970
Biochimie. 1998 Mar;80(3):235-46
pubmed: 9615863
Chem Res Toxicol. 2008 Jun;21(6):1253-60
pubmed: 18461976
Biochemistry. 2007 May 22;46(20):6097-108
pubmed: 17458941
Cancer Res. 1994 May 1;54(9):2327-30
pubmed: 8162575
Int J Mol Sci. 2015 Jan 22;16(2):2366-85
pubmed: 25622253
Front Cell Dev Biol. 2015 Jun 25;3:41
pubmed: 26161385
Mol Cell Biochem. 2003 Jan;243(1-2):153-60
pubmed: 12619901
Environ Mol Mutagen. 2019 Mar;60(2):154-167
pubmed: 30387535
Prostate. 2008 Dec 1;68(16):1773-89
pubmed: 18726985
Blood. 1996 Mar 1;87(5):1912-22
pubmed: 8634439
Leukemia. 2009 Aug;23(8):1490-9
pubmed: 19262598
Biochemistry. 1984 Mar 13;23(6):1183-8
pubmed: 6712942
Nature. 1987 Mar 19-25;326(6110):292-5
pubmed: 3821905
J Environ Pathol Toxicol Oncol. 2013;32(4):307-27
pubmed: 24579784
Toxicology. 2011 Dec 18;290(2-3):350-8
pubmed: 22064046
Biochem Biophys Res Commun. 2010 Aug 13;399(1):66-71
pubmed: 20638367
Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11014-9
pubmed: 17578914
Annu Rev Pathol. 2012;7:283-301
pubmed: 22017583
Cancer Lett. 2011 Sep 28;308(2):181-8
pubmed: 21676539
Ann N Y Acad Sci. 2014 Mar;1310:98-110
pubmed: 24495080
Virusdisease. 2015 Sep;26(3):123-32
pubmed: 26396978
Plant Foods Hum Nutr. 2004 Summer;59(3):113-22
pubmed: 15678717
J Nutr. 2000 Aug;130(8S Suppl):2073S-85S
pubmed: 10917926
PLoS Genet. 2013;9(3):e1003226
pubmed: 23505375
Nat Rev Mol Cell Biol. 2016 Nov;17(11):703-721
pubmed: 27649880