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A novel small-molecule antagonist enhances the sensitivity of osteosarcoma to cabozantinib in vitro and in vivo by targeting DNMT-1 correlated with disease severity in human patients.
- Source :
-
Pharmacological research [Pharmacol Res] 2021 Nov; Vol. 173, pp. 105869. Date of Electronic Publication: 2021 Sep 03. - Publication Year :
- 2021
-
Abstract
- Advanced osteosarcoma (OSA) is highly aggressive and can lead to distant metastasis or recurrence. Here, a novel small-molecule inhibitor/antagonist of DNA methyltransferase 1 (DNMT-1) named DI-1 (inhibitor of DNMT-1) was explored to enhance the antitumor effect of a molecular-targeted agent, cabozantinib, on OSA cell lines. In patients with OSA, expression of DNMT-1 was negatively related with that of microRNA (miR)-34a and associated with a poor prognosis. In OSA cell lines (OSA cell line U2OS and an OSA cell line U2OS <superscript>R</superscript> resistance to cabozantinib), DI-1 treatment enhanced miR-34a expression by inhibiting hypermethylation of the promoter region of miR-34a mediated by DNMT-1. DI-1 enhanced the sensitivity of OSA cells (U2OS, 143B and MG63) to cabozantinib and other molecular-targeted agents by enhancing miR-34a expression and repressing activation of the Notch pathway. Mechanistically, DI-1 repressed recruitment of DNMT-1 to the promoter region of miR-34a and, in turn, decreased the methylation rate in the promoter region of miR-34a in OSA cells. These results suggest that repressing DNMT-1 activation by DI-1 enhances miR-34a expression in OSA cells and could be a promising therapeutic strategy for OSA.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Bone Neoplasms genetics
Bone Neoplasms mortality
Bone Neoplasms pathology
Cell Line, Tumor
Cell Survival drug effects
DNA (Cytosine-5-)-Methyltransferase 1 genetics
DNA Methylation
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Humans
Mice, Nude
MicroRNAs
Osteosarcoma genetics
Osteosarcoma mortality
Osteosarcoma pathology
Prognosis
Promoter Regions, Genetic
Severity of Illness Index
Mice
Anilides administration & dosage
Antineoplastic Agents administration & dosage
Bone Neoplasms drug therapy
DNA (Cytosine-5-)-Methyltransferase 1 antagonists & inhibitors
Osteosarcoma drug therapy
Protein Kinase Inhibitors administration & dosage
Pyridines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1096-1186
- Volume :
- 173
- Database :
- MEDLINE
- Journal :
- Pharmacological research
- Publication Type :
- Academic Journal
- Accession number :
- 34481973
- Full Text :
- https://doi.org/10.1016/j.phrs.2021.105869