Τίτλος:
TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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: 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: 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: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. Funding: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé. © 2020 The Authors
Συγγραφείς:
Moukengue, B.
Brown, H.K.
Charrier, C.
Battaglia, S.
Baud'huin, M.
Quillard, T.
Pham, T.M.
Pateras, I.S.
Gorgoulis, V.G.
Helleday, T.
Heymann, D.
Berglund, U.W.
Ory, B.
Lamoureux, F.
Λέξεις-κλειδιά:
enzyme inhibitor; karonudib; mutt homolog 1 inhibitor; Nudix hydrolase; th 1579; unclassified drug; 8-oxodGTPase; antineoplastic agent; DNA; DNA ligase; karonudib; phosphatase; pyrimidine derivative, angiogenesis; animal experiment; animal model; apoptosis; Article; bone lesion; cell assay; cell migration; cell proliferation assay; cell viability; cellular thermal shift assay; clonogenic assay; comet assay; controlled study; DNA damage; enzyme activity; female; gene overexpression; human; human cell; human tissue; immunofluorescence; immunohistochemistry; in vitro study; lung metastasis; malignant neoplasm; mesenchymal stem cell; micro-computed tomography; mouse; nonhuman; osteoclast; osteosarcoma; priority journal; proof of concept; tumor cell; tumor growth; tumor volume; Western blotting; animal; bone tumor; genetics; lung tumor; metabolism; osteosarcoma; pathology; tumor cell culture; tumor cell line, 8-Hydroxy-2'-Deoxyguanosine; Animals; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Line, Tumor; DNA; DNA Repair Enzymes; Humans; Lung Neoplasms; Mice; Osteosarcoma; Phosphoric Monoester Hydrolases; Pyrimidines; Tumor Cells, Cultured
DOI:
10.1016/j.ebiom.2020.102704
