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

Cheng Yu Tsai, Huey Jiun Ko, Shean Jaw Chiou, Yu Ling Lai, Chia Chung Hou, Tehseen Javaria, Zi Yi Huang, Tai Shan Cheng, Tsung I. Hsu, Jian Ying Chuang, Aij Lie Kwan, Tsung Hsien Chuang, Chi Ying F. Huang, Joon Khim Loh, Yi Ren Hong

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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 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.

Original languageEnglish
Article number5907
JournalInternational journal of molecular sciences
Volume22
Issue number11
DOIs
Publication statusPublished - Jun 1 2021

Keywords

  • Connectivity map
  • GBM
  • HDAC8
  • MGMT
  • P53
  • TMZ
  • β-catenin

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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