TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model.
8-Hydroxy-2'-Deoxyguanosine
/ metabolism
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Bone Neoplasms
/ drug therapy
Cell Line, Tumor
DNA
/ genetics
DNA Repair Enzymes
/ antagonists & inhibitors
Humans
Lung Neoplasms
/ drug therapy
Mice
Osteosarcoma
/ drug therapy
Phosphoric Monoester Hydrolases
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
Tumor Cells, Cultured
Bone tumours
DNA damage
MTH1
Osteosarcoma
ROS
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
04
10
2019
revised:
22
01
2020
accepted:
20
02
2020
pubmed:
11
3
2020
medline:
18
12
2020
entrez:
11
3
2020
Statut:
ppublish
Résumé
Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
Sections du résumé
BACKGROUND
BACKGROUND
Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers.
METHODS
METHODS
The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases.
FINDINGS
RESULTS
MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases.
INTERPRETATION
CONCLUSIONS
All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma.
FUNDING
BACKGROUND
This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
Identifiants
pubmed: 32151797
pii: S2352-3964(20)30079-7
doi: 10.1016/j.ebiom.2020.102704
pmc: PMC7063190
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Pyrimidines
0
karonudib
0
8-Hydroxy-2'-Deoxyguanosine
88847-89-6
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
Langues
eng
Sous-ensembles de citation
IM
Pagination
102704Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Helleday, T: A patent has been filed with TH588 and TH1579 where T.H., is listed as inventor. The Intellectual Property Right is owned by the non-profit Thomas Helleday Foundation for Medical Research (THF). T.H. and U.W.B are board members of the THF. U.W.B is chairman of Oxcia AB. THF is sponsor for on-going clinical trial with TH1579.
Références
Ann Oncol. 2014 Jul;25(7):1253-1255
pubmed: 24737777
J Bone Oncol. 2019 Apr 03;16:100236
pubmed: 31024791
Cancers (Basel). 2017 May 08;9(5):
pubmed: 28481306
Expert Rev Anticancer Ther. 2007 Feb;7(2):169-81
pubmed: 17288528
Nucleic Acids Res. 2001 Jan 15;29(2):449-54
pubmed: 11139615
Cancer. 1976 Jan;37(1):1-11
pubmed: 1082364
Korean J Pediatr. 2015 Apr;58(4):123-8
pubmed: 25932033
Oxid Med Cell Longev. 2017;2017:8416763
pubmed: 28819546
Asian Pac J Cancer Prev. 2014;15(15):5967-76
pubmed: 25124559
Anticancer Drugs. 2018 Apr;29(4):341-352
pubmed: 29420337
J Biol Chem. 2001 Nov 9;276(45):42462-7
pubmed: 11571274
J Exp Clin Cancer Res. 2018 May 21;37(1):107
pubmed: 29784019
BMC Cancer. 2018 Nov 29;18(1):1190
pubmed: 30497423
Oncogene. 2011 Mar 24;30(12):1489-96
pubmed: 21076467
J Bone Oncol. 2018 Jul 26;12:83-90
pubmed: 30123735
Sci Rep. 2019 Jan 28;9(1):819
pubmed: 30692572
Ann Oncol. 2016 Dec;27(12):2275-2283
pubmed: 27827301
Blood. 1949 Feb;4(2):160-7
pubmed: 18107667
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):169-74
pubmed: 19118192
Apoptosis. 2017 Nov;22(11):1321-1335
pubmed: 28936716
J Am Med Assoc. 1946 Sep 21;132:126-32
pubmed: 20997191
DNA Repair (Amst). 2015 Sep;33:101-10
pubmed: 26202347
Nature. 2014 Apr 10;508(7495):222-7
pubmed: 24695225
Chem Biol. 2013 May 23;20(5):648-59
pubmed: 23706631
Cell Death Dis. 2019 Jun 4;10(6):434
pubmed: 31164636
Mutagenesis. 2010 Sep;25(5):463-71
pubmed: 20534734
BMC Cancer. 2018 Apr 16;18(1):423
pubmed: 29661172
Bone. 2017 Jan;94:10-21
pubmed: 27669656
Semin Cell Dev Biol. 2018 Aug;80:50-64
pubmed: 28587975
Curr Opin Genet Dev. 2002 Apr;12(2):162-9
pubmed: 11893489
Calcif Tissue Int. 2018 Feb;102(2):174-195
pubmed: 29238848
Oncotarget. 2017 Jul 20;8(49):84671-84684
pubmed: 29156675
Front Biosci. 2005 May 01;10:1881-96
pubmed: 15769673
Sci Rep. 2016 May 23;6:26521
pubmed: 27210421
Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11456-61
pubmed: 11572992
Science. 2013 Jul 5;341(6141):84-7
pubmed: 23828940
Anal Biochem. 1998 Jan 1;255(1):20-31
pubmed: 9448838
Free Radic Res. 2010 May;44(5):479-96
pubmed: 20370557
Bioorg Med Chem Lett. 2016 Mar 15;26(6):1503-1507
pubmed: 26898335
Nature. 2014 Apr 10;508(7495):215-21
pubmed: 24695224
J Med Chem. 2016 Mar 24;59(6):2346-61
pubmed: 26878898
Free Radic Biol Med. 2017 Jun;107:151-158
pubmed: 27833032
DNA Repair (Amst). 2018 Sep;69:53-62
pubmed: 30055508
Mutat Res. 2010 Nov 28;703(1):51-8
pubmed: 20542142
Int J Mol Sci. 2017 Sep 15;18(9):
pubmed: 28914798