The novel dual BET/HDAC inhibitor TW09 mediates cell death by mitochondrial apoptosis in rhabdomyosarcoma cells
| Autor: | Stefan Knapp, Cathinka Boedicker, Simone Fulda, Stephanie Laszig, Tim Weiser |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Antineoplastic Agents Apoptosis 03 medical and health sciences 0302 clinical medicine Puma Cell Line Tumor Rhabdomyosarcoma Humans Viability assay Caspase bcl-2-Associated X Protein Membrane Potential Mitochondrial biology Chemistry Proteins biology.organism_classification Bromodomain Mitochondria Histone Deacetylase Inhibitors 030104 developmental biology Oncology Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Caspases Cancer cell Cancer research biology.protein Histone deacetylase biological phenomena cell phenomena and immunity |
| Zdroj: | Cancer letters. 486 |
| ISSN: | 1872-7980 |
| Popis: | Targeting the epigenome of cancer cells with the combination of Bromodomain and Extra Terminal (BET) protein inhibitors and histone deacetylase (HDAC) inhibitors has shown synergistic antitumor effects in several cancer types. In this study, we investigate the antitumor potential of the novel dual BET/HDAC inhibitor TW09 in rhabdomyosarcoma (RMS) cells. TW09 reduces cell viability, suppresses long-term clonogenic survival and induces cell death in RMS cells in a dose-dependent manner. Compared to BET/HDAC co-inhibition using JQ1 and MS-275, TW09 induces similar cell death at equimolar concentrations and regulates BET and HDAC target proteins (e.g. c-MYC, H3 acetylation). Mechanistic studies revealed that TW09 upregulates BIM, NOXA, PUMA and BMF, while downregulating BCL-XL, leading to proapoptotic rebalancing of BCL-2 proteins. This results in BAK and BAX activation and caspase-dependent apoptosis, since individual genetic silencing of BIM, NOXA, PUMA, BMF, BAK or BAX, overexpression of BCL-2 or the caspase inhibition with zVAD.fmk all rescue JQ1/BYL719-induced cell death. In conclusion, TW09 shows potent antitumor activity in RMS cells in vitro by inducing mitochondrial apoptosis and may represent a promising new therapeutic option for the treatment of RMS. |
| Databáze: | OpenAIRE |
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