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

• DOI: 10.1186/s12964-022-01007-x
• Publication Date: 2022-12-27T09:03:14Z
• Authors: 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
• Keywords: Temozolomide

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 CRC we examined effects of various inhibitors (HDAC8i), including BMX (NBM-T-L-BMX-OS01) combination temozolomide (TMZ) or other standard drugs on p53 mutated HT29 cells, well wild-type HCT116 and RKO cells. Results We showed that HDAC8i TMZ cotreatment resulted arrest S G2/M phase, whereas G0/G1 phase was accompanied by high sub-G1. Subsequently, this approach upregulated p53-mediated MGMT inhibition, leading to apoptosis. Furthermore, observed also enabled triggering cell senescence decreased expression stem biomarkers. Mechanistically, found down-expression levels β-catenin, cyclin D1 c-Myc via GSK3β/β-catenin signaling. Intriguingly, autophagy contributes death under opposite status β-catenin/p62 axis, suggesting exists negative feedback regulation between Wnt/β-catenin autophagy. Consistently, Gene Set Enrichment Analysis (GSEA) indicated both apoptotic biomarkers were after treating BMX. Conclusions may act eraser reframed-TMZ generates remarkable synergic effect, providing novel target CRCs.