Cellular mechanism of action of 2-nitroimidazoles as hypoxia-selective therapeutic agents.
Head and neck tumour
Hypoxia
Nitroimidazole
Replication stress
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
06
01
2022
revised:
05
03
2022
accepted:
18
03
2022
pubmed:
18
4
2022
medline:
11
5
2022
entrez:
17
4
2022
Statut:
ppublish
Résumé
Solid tumours are often poorly oxygenated, which confers resistance to standard treatment modalities. Targeting hypoxic tumours requires compounds, such as nitroimidazoles (NIs), equipped with the ability to reach and become activated within diffusion limited tumour niches. NIs become selectively entrapped in hypoxic cells through bioreductive activation, and have shown promise as hypoxia directed therapeutics. However, little is known about their mechanism of action, hindering the broader clinical usage of NIs. Iodoazomycin arabinofuranoside (IAZA) and fluoroazomycin arabinofuranoside (FAZA) are clinically validated 2-NI hypoxic radiotracers with excellent tumour uptake properties. Hypoxic cancer cells have also shown preferential susceptibility to IAZA and FAZA treatment, making them ideal candidates for an in-depth study in a therapeutic setting. Using a head and neck cancer model, we show that hypoxic cells display higher sensitivity to IAZA and FAZA, where the drugs alter cell morphology, compromise DNA replication, slow down cell cycle progression and induce replication stress, ultimately leading to cytostasis. Effects of IAZA and FAZA on target cellular macromolecules (DNA, proteins and glutathione) were characterized to uncover potential mechanism(s) of action. Covalent binding of these NIs was only observed to cellular proteins, but not to DNA, under hypoxia. While protein levels remained unaffected, catalytic activities of NI target proteins, such as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the detoxification enzyme glutathione S-transferase (GST) were significantly curtailed in response to drug treatment under hypoxia. Intraperitoneal administration of IAZA was well-tolerated in mice and produced early (but transient) growth inhibition of subcutaneous mouse tumours.
Identifiants
pubmed: 35430547
pii: S2213-2317(22)00072-6
doi: 10.1016/j.redox.2022.102300
pmc: PMC9038562
pii:
doi:
Substances chimiques
Nitroimidazoles
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
102300Subventions
Organisme : CIHR
ID : MOP-36519
Pays : Canada
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Références
Eur J Nucl Med Mol Imaging. 2009 Oct;36(10):1565-73
pubmed: 19430784
Mutagenesis. 2011 Mar;26(2):253-60
pubmed: 21068206
J Nucl Med. 1991 Sep;32(9):1764-70
pubmed: 1880579
Chem Biol Interact. 1984 Apr;49(1-2):13-25
pubmed: 6722933
Cancer Res. 1980 Jul;40(7):2165-9
pubmed: 6155991
Int J Parasitol Drugs Drug Resist. 2012 May 12;2:166-70
pubmed: 24533278
Nat Cell Biol. 2014 Jan;16(1):2-9
pubmed: 24366029
Front Cell Dev Biol. 2021 May 10;9:670392
pubmed: 34041245
Curr Mol Med. 2009 May;9(4):442-58
pubmed: 19519402
Toxicol Lett. 2019 Mar 1;302:28-34
pubmed: 30562549
Nat Protoc. 2009;4(12):1798-806
pubmed: 20010931
Commun Biol. 2020 Aug 17;3(1):450
pubmed: 32807853
Nucleic Acids Res. 2021 Jan 25;49(2):928-953
pubmed: 33406258
Cell Stress Chaperones. 2009 Mar;14(2):183-92
pubmed: 18726712
Med Chem. 2009 Mar;5(2):118-29
pubmed: 19275710
Biochem Pharmacol. 1987 Oct 1;36(19):3299-304
pubmed: 3663242
J Biol Chem. 2014 Feb 28;289(9):5758-73
pubmed: 24415753
Radiother Oncol. 1998 Feb;46(2):135-46
pubmed: 9510041
Anticancer Res. 2005 May-Jun;25(3B):2145-51
pubmed: 16158957
Br J Radiol. 1973 Aug;46(548):623-30
pubmed: 4798767
Free Radic Biol Med. 2007 Apr 15;42(8):1165-77
pubmed: 17382198
Nucleosides Nucleotides Nucleic Acids. 2019;38(7):449-480
pubmed: 30689502
Med Oncol. 2001;18(4):243-59
pubmed: 11918451
J Antimicrob Chemother. 2018 Feb 1;73(2):265-279
pubmed: 29077920
J Nucl Med. 2014 Nov;55(11):1772-7
pubmed: 25324522
Br J Cancer. 1979 Mar;39(3):321-9
pubmed: 465301
PLoS Biol. 2007 Aug;5(8):e211
pubmed: 17676992
Cancer Res. 1983 Jan;43(1):78-82
pubmed: 6847786
Cytometry. 1993 Nov;14(8):876-82
pubmed: 7904555
Neurol Int. 2016 Apr 01;8(1):6365
pubmed: 27127600
Acta Pharmacol Sin. 2017 Dec;38(12):1642-1654
pubmed: 28713155
Redox Biol. 2021 May;41:101905
pubmed: 33640700
Lancet Oncol. 2005 Oct;6(10):757-64
pubmed: 16198981
Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):1065-8
pubmed: 2649462
Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):567-76
pubmed: 7790241
Eur J Nucl Med Mol Imaging. 2007 Oct;34(10):1566-75
pubmed: 17447061
Mol Cell Biol. 1995 May;15(5):2612-24
pubmed: 7739542
J Biol Chem. 2001 Dec 21;276(51):47759-62
pubmed: 11673449
Int J Radiat Biol Relat Stud Phys Chem Med. 1985 Apr;47(4):379-82
pubmed: 2985519
Biochem Pharmacol. 1985 Oct 1;34(19):3537-42
pubmed: 3902026
Radiother Oncol. 2012 Jan;102(1):122-9
pubmed: 21996521
Antioxid Redox Signal. 2014 Oct 1;21(10):1516-54
pubmed: 24512032
Mol Microbiol. 2009 Apr;72(2):518-36
pubmed: 19415801
Cancers (Basel). 2020 Dec 23;13(1):
pubmed: 33374581
Biochem J. 2013 Sep 1;454(2):201-8
pubmed: 23772801
Cold Spring Harb Perspect Biol. 2017 Jul 5;9(7):
pubmed: 28679638
Int J Oncol. 2017 Jan;50(1):252-262
pubmed: 27878251
J Infect Dis. 1983 Dec;148(6):1083-9
pubmed: 6197496
J Pharmacol Exp Ther. 2009 Oct;331(1):77-86
pubmed: 19628630
Cancer Res. 1999 Dec 1;59(23):5863-70
pubmed: 10606224
Pharmaceuticals (Basel). 2019 Feb 15;12(1):
pubmed: 30781409
Cancers (Basel). 2018 Apr 15;10(4):
pubmed: 29662021
J Antimicrob Chemother. 1976 Jun;2(2):203-9
pubmed: 956083
Int J Mol Med. 2011 Mar;27(3):345-52
pubmed: 21181092
Sci Rep. 2015 Nov 19;5:16802
pubmed: 26582591
Biophys Chem. 2017 Jun;225:3-9
pubmed: 27939387
Nat Rev Cancer. 2011 Jun;11(6):393-410
pubmed: 21606941
Head Neck. 2007 Jun;29(6):591-604
pubmed: 17252597
Clin Oncol (R Coll Radiol). 2014 May;26(5):277-88
pubmed: 24602562
Biomacromolecules. 2015 Jul 13;16(7):1978-86
pubmed: 25996799
Cold Spring Harb Protoc. 2016 Apr 01;2016(4):pdb.prot087379
pubmed: 27037069
Oncol Res. 1994;6(10-11):509-18
pubmed: 7620219
Cell Syst. 2016 Feb 24;2(2):112-121
pubmed: 26942229
Radiother Oncol. 1996 Oct;41(1):31-9
pubmed: 8961365
Cell Res. 2015 Jan;25(1):9-23
pubmed: 25403473
Cancer Sci. 2009 Aug;100(8):1366-73
pubmed: 19459851
Br J Radiol. 2014 Mar;87(1035):20130676
pubmed: 24588669
Biochem Pharmacol. 1986 Nov 15;35(22):3923-8
pubmed: 3778516