Cytotoxic Components from Hypericum elodeoides Targeting RXRα and Inducing HeLa Cell Apoptosis through Caspase-8 Activation and PARP Cleavage
| Autor: | Daren Qiu, Yujie Huang, Mi Zhou, Wen-Jing Tian, Guanghui Wang, Xin Jiang, Hai-Feng Chen, Junjie Chen, Ting Lin |
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| Rok vydání: | 2019 |
| Předmět: |
Magnetic Resonance Spectroscopy
Pharmaceutical Science Apoptosis Caspase 8 01 natural sciences Analytical Chemistry HeLa Structure-Activity Relationship Enzyme activator Western blot Transcription (biology) Drug Discovery medicine Humans Structure–activity relationship Cytotoxic T cell Pharmacology Retinoid X Receptor alpha Dose-Response Relationship Drug medicine.diagnostic_test biology 010405 organic chemistry Chemistry Organic Chemistry biology.organism_classification Antineoplastic Agents Phytogenic 0104 chemical sciences Cell biology Enzyme Activation Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Complementary and alternative medicine Molecular Medicine Poly(ADP-ribose) Polymerases Hypericum HeLa Cells |
| Zdroj: | Journal of Natural Products. 82:1072-1080 |
| ISSN: | 1520-6025 0163-3864 |
| Popis: | To find small-molecule regulators of RXRα, a phytochemical study of Hypericum elodeoides was conducted. Fifteen compounds, including the new 1 and 6, were isolated from the whole plant of H. elodeoides. The absolute configuration of 1 was assigned by comparison of experimental and calculated ECD data. Compounds 1 and 6 exhibited concentration-dependent inhibitory effects on RXRα transcription and selectively inhibited the proliferation of HeLa cells. Western blot analysis suggested that 1 and 6 induced apoptosis of HeLa cells with time- and dose-dependent PARP cleavage. A caspase activation assay indicated that these two compounds triggered caspase-8 activation to induce apoptosis by the extrinsic pathway. Molecular docking results suggested that 1 and 6 interacted with the Arg319 moiety of RXRα-LBD. Ligands binding to RXRα have shown promise in the discovery of anticancer drugs. A fluorescence quenching assay indicated the binding of 1 and 6 to the RXRα with the binding constant ( KD) fitted as 68.3 and 14.0 μM, respectively. A preliminary SAR study of the isolates was conducted to enhance the knowledge of the RXRα ligands. Thus, 1 and 6 might act as the small-molecule regulators of RXRα, which target RXRα and mediate HeLa cell apoptosis through the extrinsic pathways. |
| Databáze: | OpenAIRE |
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