Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma.
Animals
Apoptosis
/ drug effects
Burkitt Lymphoma
/ drug therapy
Cell Cycle Checkpoints
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
DNA
/ biosynthesis
DNA Repair Enzymes
/ antagonists & inhibitors
Deoxyguanine Nucleotides
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Lymphoma, B-Cell
/ drug therapy
Mice
Phosphoric Monoester Hydrolases
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
Xenograft Model Antitumor Assays
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 03 2021
18 03 2021
Historique:
received:
22
09
2020
accepted:
23
02
2021
entrez:
19
3
2021
pubmed:
20
3
2021
medline:
12
10
2021
Statut:
epublish
Résumé
Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.
Identifiants
pubmed: 33737576
doi: 10.1038/s41598-021-85613-8
pii: 10.1038/s41598-021-85613-8
pmc: PMC7973795
doi:
Substances chimiques
Deoxyguanine Nucleotides
0
Pyrimidines
0
karonudib
0
8-oxodeoxyguanosine triphosphate
139307-94-1
DNA
9007-49-2
Phosphoric Monoester Hydrolases
EC 3.1.3.2
8-oxodGTPase
EC 3.6.1.55
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6317Subventions
Organisme : European Research Council
ID : ERC-2015-Adg_695376
Pays : International
Références
Ann Oncol. 2016 Dec;27(12):2275-2283
pubmed: 27827301
Blood. 2017 Jan 19;129(3):280-288
pubmed: 27821509
Cancer. 2018 Dec 15;124(24):4622-4632
pubmed: 30252929
J Hematol Oncol. 2018 Feb 20;11(1):23
pubmed: 29458389
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Sci Rep. 2019 Oct 11;9(1):14667
pubmed: 31604991
Nature. 2014 Apr 10;508(7495):215-21
pubmed: 24695224
J Exp Med. 2008 Sep 29;205(10):2251-68
pubmed: 18794340
N Engl J Med. 1997 Aug 21;337(8):529-34
pubmed: 9262496
Leuk Lymphoma. 2015 Jun;56(6):1742-9
pubmed: 25284491
Cell Syst. 2019 Jul 24;9(1):74-92.e8
pubmed: 31302152
J Biol Chem. 1997 Jul 11;272(28):17843-50
pubmed: 9211940
Best Pract Res Clin Haematol. 2018 Sep;31(3):279-284
pubmed: 30213397
Nucleic Acids Res. 2018 Nov 16;46(20):10888-10904
pubmed: 30304478
PLoS One. 2013 Nov 19;8(11):e79602
pubmed: 24260260
J Immunol Methods. 1992 Feb 5;146(2):195-202
pubmed: 1371532
Eur J Haematol. 2013 Oct;91(4):332-8
pubmed: 23859481
Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):366-378
pubmed: 27913503
Nature. 2000 Feb 3;403(6769):503-11
pubmed: 10676951
J Biol Chem. 1999 Jun 25;274(26):18201-5
pubmed: 10373420
Cell Cycle. 2015;14(20):3261-9
pubmed: 26317799
Blood. 2018 Oct 18;132(16):1647-1656
pubmed: 30154113
J Biol Chem. 1993 Nov 5;268(31):23524-30
pubmed: 8226881
Cancer Res. 2020 Sep 1;80(17):3530-3541
pubmed: 32312836
Ann Oncol. 2014 Jul;25(7):1253-1255
pubmed: 24737777
Cell Death Dis. 2018 Jul 24;9(8):810
pubmed: 30042422
Sci Transl Med. 2019 Sep 11;11(509):
pubmed: 31511426
Nature. 1993 Apr 29;362(6423):849-52
pubmed: 8479523
Blood. 2014 Feb 13;123(7):1051-4
pubmed: 24357726
J Biol Chem. 2003 Sep 26;278(39):37965-73
pubmed: 12857738
Int J Cancer. 2000 Jul 20;89(4):313-24
pubmed: 10956404
Nucleic Acids Res. 2001 Jan 15;29(2):449-54
pubmed: 11139615
Cell. 1993 Sep 24;74(6):957-67
pubmed: 8402885
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
N Engl J Med. 2006 Jun 8;354(23):2431-42
pubmed: 16760443
Ther Adv Med Oncol. 2019 Aug 23;11:1758835919866960
pubmed: 31489034
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
J Digit Imaging. 2004 Sep;17(3):205-16
pubmed: 15534753
J Clin Oncol. 2010 Sep 20;28(27):4184-90
pubmed: 20660832
Mutat Res. 2001 Jun 2;477(1-2):71-8
pubmed: 11376688
FEBS Lett. 2012 Sep 21;586(19):3367-72
pubmed: 22819827
Curr Protoc Cytom. 2010 Jul;Chapter 10:Unit10.17
pubmed: 20578106
Eur J Immunol. 2011 Nov;41(11):3135-45
pubmed: 21898381
Radiat Res. 2004 Oct;162(4):405-15
pubmed: 15447042
Br J Pharmacol. 2019 Feb;176(3):436-450
pubmed: 30427531
Methods Mol Biol. 2020;2115:445-454
pubmed: 32006416