The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death
Andrographolide, a medicinal compound, exhibits several pharmacological activities, including antiviral and anticancer properties. Previously, we reported that andrographolide inhibits Epstein–Barr virus (EBV) lytic reactivation, which is associated with viral transmission and oncogenesis in epithel...
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/21/15867 |
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| author | Chukkris Heawchaiyaphum Praphatson Malat Chamsai Pientong Sittiruk Roytrakul Yodying Yingchutrakul Sirinart Aromseree Supawadee Suebsasana Panupong Mahalapbutr Tipaya Ekalaksananan |
| author_facet | Chukkris Heawchaiyaphum Praphatson Malat Chamsai Pientong Sittiruk Roytrakul Yodying Yingchutrakul Sirinart Aromseree Supawadee Suebsasana Panupong Mahalapbutr Tipaya Ekalaksananan |
| author_sort | Chukkris Heawchaiyaphum |
| collection | DOAJ |
| description | Andrographolide, a medicinal compound, exhibits several pharmacological activities, including antiviral and anticancer properties. Previously, we reported that andrographolide inhibits Epstein–Barr virus (EBV) lytic reactivation, which is associated with viral transmission and oncogenesis in epithelial cancers, including head-and-neck cancer (HNC) cells. However, the underlying mechanism through which andrographolide inhibits EBV lytic reactivation and affects HNC cells is poorly understood. Therefore, we investigated these mechanisms using EBV-positive HNC cells and the molecular modeling and docking simulation of protein. Based on the results, the expression of EBV lytic genes and viral production were significantly inhibited in andrographolide-treated EBV-positive HNC cells. Concurrently, there was a reduction in transcription factors (TFs), myocyte enhancer factor-2D (MEF2D), specificity protein (SP) 1, and SP3, which was significantly associated with a combination of andrographolide and sodium butyrate (NaB) treatment. Surprisingly, andrographolide treatment also significantly induced the expression of DNA Methyltransferase (DNMT) 1, DNMT3B, and histone deacetylase (HDAC) 5 in EBV-positive cells. Molecular modeling and docking simulation suggested that HDAC5 could directly interact with MEF2D, SP1, and SP3. In our in vitro study, andrographolide exhibited a stronger cytotoxic effect on EBV-positive cells than EBV-negative cells by inducing cell death. Interestingly, the proteome analysis revealed that the expression of RIPK1, RIPK3, and MLKL, the key molecules for necroptosis, was significantly greater in andrographolide-treated cells. Taken together, it seems that andrographolide exhibits concurrent activities in HNC cells; it inhibits EBV lytic reactivation by interrupting the expression of TFs and induces cell death, probably via necroptosis. |
| first_indexed | 2024-03-11T11:27:31Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:27:31Z |
| publishDate | 2023-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8d5932bfda024c01a82a9ac15275b7872023-11-10T15:05:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124211586710.3390/ijms242115867The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell DeathChukkris Heawchaiyaphum0Praphatson Malat1Chamsai Pientong2Sittiruk Roytrakul3Yodying Yingchutrakul4Sirinart Aromseree5Supawadee Suebsasana6Panupong Mahalapbutr7Tipaya Ekalaksananan8Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandDepartment of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandDepartment of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandFunctional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, ThailandFunctional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, ThailandFaculty of Agriculture and Technology, Nakhon Phanom University, Nakhon Phanom 48000, ThailandDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, Rangsit Center, Thammasat University, Pathum Thani 12120, ThailandDepartment of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandDepartment of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandAndrographolide, a medicinal compound, exhibits several pharmacological activities, including antiviral and anticancer properties. Previously, we reported that andrographolide inhibits Epstein–Barr virus (EBV) lytic reactivation, which is associated with viral transmission and oncogenesis in epithelial cancers, including head-and-neck cancer (HNC) cells. However, the underlying mechanism through which andrographolide inhibits EBV lytic reactivation and affects HNC cells is poorly understood. Therefore, we investigated these mechanisms using EBV-positive HNC cells and the molecular modeling and docking simulation of protein. Based on the results, the expression of EBV lytic genes and viral production were significantly inhibited in andrographolide-treated EBV-positive HNC cells. Concurrently, there was a reduction in transcription factors (TFs), myocyte enhancer factor-2D (MEF2D), specificity protein (SP) 1, and SP3, which was significantly associated with a combination of andrographolide and sodium butyrate (NaB) treatment. Surprisingly, andrographolide treatment also significantly induced the expression of DNA Methyltransferase (DNMT) 1, DNMT3B, and histone deacetylase (HDAC) 5 in EBV-positive cells. Molecular modeling and docking simulation suggested that HDAC5 could directly interact with MEF2D, SP1, and SP3. In our in vitro study, andrographolide exhibited a stronger cytotoxic effect on EBV-positive cells than EBV-negative cells by inducing cell death. Interestingly, the proteome analysis revealed that the expression of RIPK1, RIPK3, and MLKL, the key molecules for necroptosis, was significantly greater in andrographolide-treated cells. Taken together, it seems that andrographolide exhibits concurrent activities in HNC cells; it inhibits EBV lytic reactivation by interrupting the expression of TFs and induces cell death, probably via necroptosis.https://www.mdpi.com/1422-0067/24/21/15867andrographolideEBVEBV lytic reactivationHDAC5MEF2DSP1 |
| spellingShingle | Chukkris Heawchaiyaphum Praphatson Malat Chamsai Pientong Sittiruk Roytrakul Yodying Yingchutrakul Sirinart Aromseree Supawadee Suebsasana Panupong Mahalapbutr Tipaya Ekalaksananan The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death International Journal of Molecular Sciences andrographolide EBV EBV lytic reactivation HDAC5 MEF2D SP1 |
| title | The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death |
| title_full | The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death |
| title_fullStr | The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death |
| title_full_unstemmed | The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death |
| title_short | The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death |
| title_sort | dual functions of andrographolide in the epstein barr virus positive head and neck cancer cells the inhibition of lytic reactivation of the epstein barr virus and the induction of cell death |
| topic | andrographolide EBV EBV lytic reactivation HDAC5 MEF2D SP1 |
| url | https://www.mdpi.com/1422-0067/24/21/15867 |
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