TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

EBioMedicine
Brice MoukengueFrancois Lamoureux

Abstract

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 ce...Continue Reading

References

Feb 4, 1998·Analytical Biochemistry·L StruthersS Thomas
Jan 5, 2001·Nucleic Acids Research·K FujikawaH Kasai
Sep 26, 2001·The Journal of Biological Chemistry·S BurmaD J Chen
Sep 27, 2001·Proceedings of the National Academy of Sciences of the United States of America·T TsuzukiM Sekiguchi
Mar 15, 2002·Current Opinion in Genetics & Development·Christophe RedonWilliam Bonner
Mar 17, 2005·Frontiers in Bioscience : a Journal and Virtual Library·Peter Storz
Feb 10, 2007·Expert Review of Anticancer Therapy·François LamoureuxFrançoise Redini
Jan 2, 2009·Proceedings of the National Academy of Sciences of the United States of America·Priyamvada RaiRobert A Weinberg
Apr 8, 2010·Free Radical Research·Geou-Yarh Liou, Peter Storz
May 28, 2013·Chemistry & Biology·Kahlin Cheung-OngCorey Nislow
Apr 4, 2014·Nature·Kilian V M HuberGiulio Superti-Furga
Aug 16, 2014·Asian Pacific Journal of Cancer Prevention : APJCP·Jin-Peng HeJie-Xiong Feng
May 2, 2015·Korean journal of pediatrics·Jun Ah Lee
Feb 18, 2016·Journal of Medicinal Chemistry·Jason G KettleMarta Wylot
Feb 24, 2016·Bioorganic & Medicinal Chemistry Letters·Alessia PetrocchiRichard T Lewis
Nov 9, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·U Warpman BerglundT Helleday
Nov 12, 2016·Free Radical Biology & Medicine·Yusaku NakabeppuNona Abolhassani
Jun 8, 2017·Seminars in Cell & Developmental Biology·Jennifer N Moloney, Thomas G Cotter
Aug 19, 2017·Oxidative Medicine and Cellular Longevity·Gabriele PizzinoAlessandra Bitto
Sep 16, 2017·International Journal of Molecular Sciences·Anastasios GeorgoulisEmmy P Rogakou
Sep 25, 2017·Apoptosis : an International Journal on Programmed Cell Death·Zhengzhi ZouSongmao Wang
Nov 22, 2017·Oncotarget·Linda PudelkoLars Bräutigam
Dec 15, 2017·Calcified Tissue International·Hannah K BrownDominique Heymann
May 23, 2018·Journal of Experimental & Clinical Cancer Research : CR·Hye Jeong ParkKyu Yun Jang
Jul 29, 2018·DNA Repair·Katarzyna D ArczewskaBarbara Czarnocka
Aug 21, 2018·Journal of Bone Oncology·Antoine ChalopinDominique Heymann
Jan 30, 2019·Scientific Reports·Lizet M van der WaalsOnno Kranenburg
Jun 6, 2019·Cell Death & Disease·Wenjuan ZhouWen Zhao
Jul 1, 2014·Annals of Oncology : Official Journal of the European Society for Medical Oncology·T Helleday

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Citations

Feb 3, 2021·International Journal of Molecular Sciences·Hui ShiYosuke Taniguchi
Jan 16, 2021·Redox Biology·Ling ZhangPriyamvada Rai
Mar 7, 2021·International Journal of Molecular Sciences·Roni H G Wright, Miguel Beato
Oct 2, 2021·Cancer Research·Kumar SanjivUlrika Warpman Berglund

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Methods Mentioned

BETA
xenograft
biopsy
transfection
flow cytometry
electrophoresis
PCR
X-ray
thermal shift
biopsies
Assay

Clinical Trials Mentioned

NCT03036228

Software Mentioned

Open
Empiria Studio
ImageJ
Anova
Graphpad Prism
Skyscan
Skyscan NRecon
Skyscan CT Analyzer ( CTAn )
Odyssey

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