A novel histone deacetylase inhibitor MPT0L184 dysregulates cell-cycle checkpoints and initiates unscheduled mitotic signaling - 16/04/21
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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.
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Highlights |
• | MPT0L184 exhibits high toxicity in various cancer cell lines including gastric cancer cells resistant to HDAC inhibitors. |
• | MPT0L184 shows tumor-suppressing activity in a tumor xenograft mouse model. |
• | MPT0L184 possesses strong inhibitory activity toward HDAC1 and 2. |
• | MPT0L184 treatment leads to an early onset of mitosis. |
• | MPT0L184 treatment downregulates WEE1 expression and ATR/CHK1 signaling. |
Keywords : Histone deacetylases (HDACs), MPT0L184, Checkpoint kinases, Cyclin-dependent kinases (CDKs), Premature mitosis, Drug resistance
Esquema
Vol 138
Artículo 111485- juin 2021 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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