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. (November 2021)

• Record Type: Journal Article
• Authors: Wang, Ji-Hai; Zeng, Zhen; Sun, Jie; Chen, Yan; Gao, Xudong
• Is Part Of: Pharmacological research. Volume 173(2021)
• Publication Date: 2021-11
• Subjects: Osteosarcoma -- Cabozantinib -- DNMT-1 -- miR-34a/Notch axis -- Promoter methylation -- Small molecular inhibitors; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105869
• Languages: English
• ISSNs: 1043-6618

Abstract

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 R 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. Graphical Abstract: ga1 Highlights: A novel small-molecule inhibitor of DNMT-1 named DI-1 was explored. In OSA cells, DI-1 represses the activation of DNMT-1. DI-1 treatment enhanced miR-34a expression by inhibiting hypermethylation of the promoter region of miR-34a. DI-1 enhanced the sensitivity of OSA cells to cabozantinib and other molecular-targeted agents.