摘要
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.].
原文 | 英語 |
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文章編號 | 200 |
期刊 | Cell Communication and Signaling |
卷 | 20 |
發行號 | 1 |
DOIs | |
出版狀態 | 已發佈 - 2022 12月 |
ASJC Scopus subject areas
- 生物化學
- 分子生物學
- 細胞生物學
指紋
深入研究「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」主題。共同形成了獨特的指紋。資料集
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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
Ko, H.-J. (Creator), Chiou, S.-J. (Creator), Tsai, C.-Y. (Creator), Loh, J.-K. (Creator), Lin, X.-Y. (Creator), Tran, T.-H. (Creator), Hou, C.-C. (Creator), Cheng, T.-S. (Creator), Lai, J.-M. (Creator), Chang, P.M.-H. (Creator), Wang, F.-S. (Creator), Su, C.-L. (Creator), Huang, C.-Y. F. (Creator) & Hong, Y.-R. (Creator), figshare, 2023
DOI: 10.6084/m9.figshare.c.6584759.v1, https://springernature.figshare.com/collections/BMX_a_specific_HDAC8_inhibitor_with_TMZ_for_advanced_CRC_therapy_a_novel_synergic_effect_to_elicit_p53-_-catenin-_and_MGMT-dependent_apoptotic_cell_death/6584759/1
資料集: Dataset
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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
Ko, H.-J. (Creator), Chiou, S.-J. (Creator), Tsai, C.-Y. (Creator), Loh, J.-K. (Creator), Lin, X.-Y. (Creator), Tran, T.-H. (Creator), Hou, C.-C. (Creator), Cheng, T.-S. (Creator), Lai, J.-M. (Creator), Chang, P.M.-H. (Creator), Wang, F.-S. (Creator), Su, C.-L. (Creator), Huang, C.-Y. F. (Creator) & Hong, Y.-R. (Creator), figshare, 2023
DOI: 10.6084/m9.figshare.c.6584759, https://springernature.figshare.com/collections/BMX_a_specific_HDAC8_inhibitor_with_TMZ_for_advanced_CRC_therapy_a_novel_synergic_effect_to_elicit_p53-_-catenin-_and_MGMT-dependent_apoptotic_cell_death/6584759
資料集: Dataset