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NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition
| Content Provider | MDPI |
|---|---|
| Author | Tsai, Cheng-Yu Ko, Huey-Jiun Chiou, Shean-Jaw Lai, Yu-Ling Hou, Chia-Chung Javaria, Tehseen Huang, Zi-Yi Cheng, Tai-Shan Hsu, Tsung-I Chuang, Jian-Ying Kwan, Aij-Lie Chuang, Tsung-Hsien Huang, Chi-Ying Loh, Joon-Khim Hong, Yi-Ren |
| Copyright Year | 2021 |
| Description | 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 β-catenin was reversed by proteasome inhibitor via the β-catenin/ GSK3β 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 β-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. |
| Starting Page | 5907 |
| e-ISSN | 14220067 |
| DOI | 10.3390/ijms22115907 |
| Journal | International Journal of Molecular Sciences |
| Issue Number | 11 |
| Volume Number | 22 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-05-31 |
| Access Restriction | Open |
| Subject Keyword | International Journal of Molecular Sciences Oncology Hdac8 Gbm Tmz Mgmt Connectivity Map Β-catenin P53 |
| Content Type | Text |
| Resource Type | Article |
