Synergistic antitumor activity of artesunate and HDAC inhibitors through elevating heme synthesis via synergistic upregulation of ALAS1 expression
| Autor: | Feng Zhiqi, Xiaoan Wen, Caiping Chen, Hongbin Sun, Kun Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
CMCNa
carboxymethyl cellulose Artesunate HDAC histone deacetylase chemistry.chemical_compound 0302 clinical medicine ALAS 5-aminolevulinate synthase GSDME gasdermin E General Pharmacology Toxicology and Pharmaceutics Cytotoxicity Heme 0303 health sciences LBH589 panobinostat ATP synthase biology Chemistry ART artemisinin SA succinyl acetone HDACi HDAC inhibitor ALAD 5-aminolevulinate dehydratase DHA dihydroartemisinin DMAB (dimethylamino)benzaldehyde PDT photodynamic therapy 030220 oncology & carcinogenesis PpIX protoporphyrin IX Programmed cell death Original article PI propidium iodide 03 medical and health sciences FECH ferrochelatase ROS reactive oxygen species Downregulation and upregulation HDAC inhibitor SAHA vorinostat HMBS hydroxymethylbilane synthase 030304 developmental biology KD knockdown ARS artesunate KO knockout lcsh:RM1-950 sgRNA single guide RNA CI combination index Antitumor WT wild-type ALAS1 lcsh:Therapeutics. Pharmacology Cancer research biology.protein ALA 5-aminolevulinic acid Histone deacetylase CCK-8 cell counting kit 8 Homeostasis |
| Zdroj: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 9, Iss 5, Pp 937-951 (2019) |
| ISSN: | 2211-3843 2211-3835 |
| Popis: | Artemisinin and its derivatives (ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors (HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in non-erythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate (ARS) might have synergistic antitumor activity through modulating heme synthesis. In vitro studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase (ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down ALAS1 significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors. Graphical abstract HDAC inhibitors (HDACi) cooperate with artesunate (ARS) to synergistically induce tumor cell death through promoting ALAS1 expression and subsequent heme synthesis, leading to enhanced cytotoxicity of ARS. This finding demonstrates a promising therapeutic approach to solid tumors based on modulating heme synthesis by the combination of artemisinin derivatives with HDACi.Image 1 |
| Databáze: | OpenAIRE |
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