BMX, a specific HDAC8 inhibitor, with TMZ for advanced CRC therapy: a novel synergic effect to elicit p53-, β-catenin- and MGMT-dependent apoptotic cell death

Huey Jiun Ko, Shean Jaw Chiou, Cheng Yu Tsai, Joon Khim Loh, Xin Yi Lin, Thu Ha Tran, Chia Chung Hou, Tai Shan Cheng, Jin Mei Lai, Peter Mu Hsin Chang, Feng Sheng Wang, Chun Li Su, Chi Ying F. Huang*, Yi Ren Hong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Background: Despite advances in treatment, patients with refractory colorectal cancer (CRC) still have poor long-term survival, so there is a need for more effective therapeutic options. Methods: To evaluate the HDAC8 inhibition efficacy as a CRC treatment, we examined the effects of various HDAC8 inhibitors (HDAC8i), including BMX (NBM-T-L-BMX-OS01) in combination with temozolomide (TMZ) or other standard CRC drugs on p53 mutated HT29 cells, as well as wild-type p53 HCT116 and RKO cells. Results: We showed that HDAC8i with TMZ cotreatment resulted in HT29 arrest in the S and G2/M phase, whereas HCT116 and RKO arrest in the G0/G1 phase was accompanied by high sub-G1. Subsequently, this combination approach upregulated p53-mediated MGMT inhibition, leading to apoptosis. Furthermore, we observed the cotreatment also enabled triggering of cell senescence and decreased expression of stem cell biomarkers. Mechanistically, we found down-expression levels of β-catenin, cyclin D1 and c-Myc via GSK3β/β-catenin signaling. Intriguingly, autophagy also contributes to cell death under the opposite status of β-catenin/p62 axis, suggesting that there exists a negative feedback regulation between Wnt/β-catenin and autophagy. Consistently, the Gene Set Enrichment Analysis (GSEA) indicated both apoptotic and autophagy biomarkers in HT29 and RKO were upregulated after treating with BMX. Conclusions: BMX may act as a HDAC8 eraser and in combination with reframed-TMZ generates a remarkable synergic effect, providing a novel therapeutic target for various CRCs. [MediaObject not available: see fulltext.].

Original languageEnglish
Article number200
JournalCell Communication and Signaling
Volume20
Issue number1
DOIs
Publication statusPublished - 2022 Dec

Keywords

  • CRC
  • HDAC8 inhibitor
  • MGMT
  • TMZ
  • p53
  • β-catenin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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