NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the ß-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition.
Int J Mol Sci
; 22(11)2021 May 31.
Article
de En
| MEDLINE
| ID: mdl-34072831
ABSTRACT
Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of ß-catenin was reversed by proteasome inhibitor via the ß-catenin/ GSK3ß signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the ß-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines de répression
/
DNA modification methylases
/
Protéine p53 suppresseur de tumeur
/
Glioblastome
/
Protéines suppresseurs de tumeurs
/
Enzymes de réparation de l'ADN
/
Bêta-Caténine
/
Histone deacetylases
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Int J Mol Sci
Année:
2021
Type de document:
Article
Pays d'affiliation:
Taïwan