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| 題名: | A novel histone deacetylase inhibitor MPT0L184 dysregulates cell-cycle checkpoints and initiates unscheduled mitotic signaling |
| 作者: | 李松柏
Ting-Yu Chang, Kunal Nepali, Yi-Ying Chen, Yu-Chen S.H. Yang, Kai-Cheng Hsu, Yun Yen, Shiow-Lin Pan, Jing-Ping Liou, Sung-Bau Lee |
| 貢獻者: | 新藥研發產業博士學位學程 |
| 關鍵詞: | Keywords: Histone deacetylases (HDACs);MPT0L184, Checkpoint kinases;Cyclin-dependent kinases (CDKs);Premature mitosis;Drug resistance |
| 日期: | 2021-06 |
| 上傳時間: | 2025-04-01 18:14:40 (UTC+8) |
| 摘要: | Abstract:
Aberrant alteration of epigenetic information disturbs chromatin structure and gene function, thereby facilitating cancer development. Several drugs targeting histone deacetylases (HDACs), a group of epigenetic enzymes, have been approved for treating hematologic malignancies in the clinic. However, patients who suffer from solid tumors often respond poorly to these drugs. In this study, we report a selective entinostat derivative, MPT0L184, with potent cancer-killing activity in both cell-based and mouse xenograft models. A time-course analysis of cell-cycle progression revealed that MPT0L184 treatment elicited an early onset of mitosis but prevented the division of cells with duplicated chromosomes. We show that MPT0L184 possessed potent inhibitory activity toward HDAC1 and 2, and its HDAC-inhibitory activity was required for initiating premature mitotic signaling. HDAC inhibition by MPT0L184 reduced WEE1 expression at the transcription level. In addition, MPT0L184 treatment also downregulated ATR-mediated CHK1 phosphorylation independent of HDAC inhibition. Furthermore, gastric cancer cells resistant to HDAC inhibitors were vulnerable to MPT0L184. Taken together, our study discovers MPT0L184 as a novel HDAC inhibitor that can trigger premature mitosis and potentially counteract drug resistance of cancers. |
| 關聯: | Biomedicine & Pharmacotherapy, Volume 138, 2021, 111485 |
| 描述: | 【110-1 升等】臺北醫學大學教師升等專門著作
職別：專任
送審等級：副教授
著作送審 |
| 資料類型: | article |
| 顯示於類別: | [教師升等送審著作] 110
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