Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor
The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/6/1295 |
| _version_ | 1797594592499990528 |
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| author | Małgorzata Drzewiecka Anna Gajos-Michniewicz Grażyna Hoser Dominika Jaśniak Gabriela Barszczewska-Pietraszek Przemysław Sitarek Piotr Czarny Janusz Piekarski Maciej Radek Małgorzata Czyż Tomasz Skorski Tomasz Śliwiński |
| author_facet | Małgorzata Drzewiecka Anna Gajos-Michniewicz Grażyna Hoser Dominika Jaśniak Gabriela Barszczewska-Pietraszek Przemysław Sitarek Piotr Czarny Janusz Piekarski Maciej Radek Małgorzata Czyż Tomasz Skorski Tomasz Śliwiński |
| author_sort | Małgorzata Drzewiecka |
| collection | DOAJ |
| description | The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor—valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673—PARP1 inhibitor—PARPi) and/or Dacarbazine (DTIC—alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies. |
| first_indexed | 2024-03-11T02:25:27Z |
| format | Article |
| id | doaj.art-75e5efe888284a0a8c463a5f7fadba36 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T02:25:27Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-75e5efe888284a0a8c463a5f7fadba362023-11-18T10:35:30ZengMDPI AGGenes2073-44252023-06-01146129510.3390/genes14061295Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP InhibitorMałgorzata Drzewiecka0Anna Gajos-Michniewicz1Grażyna Hoser2Dominika Jaśniak3Gabriela Barszczewska-Pietraszek4Przemysław Sitarek5Piotr Czarny6Janusz Piekarski7Maciej Radek8Małgorzata Czyż9Tomasz Skorski10Tomasz Śliwiński11Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandDepartment of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, PolandDepartment of Flow Cytometry, Medical Center for Postgraduate Education, 01-813 Warsaw, PolandLaboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandLaboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandDepartment of Medical Biology, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, PolandDepartment of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, PolandDepartment of Surgical Oncology, Medical University of Lodz, 90-419 Lodz, PolandDepartment of Neurosurgery, Surgery of Spine and Peripheral Nerves, Medical University of Lodz, University Hospital WAM-CSW, 90-549 Lodz, PolandDepartment of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, PolandFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USALaboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, PolandThe inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor—valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673—PARP1 inhibitor—PARPi) and/or Dacarbazine (DTIC—alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.https://www.mdpi.com/2073-4425/14/6/1295melanomaHDACiPARP1valproic acidalkylating agentDNA damage |
| spellingShingle | Małgorzata Drzewiecka Anna Gajos-Michniewicz Grażyna Hoser Dominika Jaśniak Gabriela Barszczewska-Pietraszek Przemysław Sitarek Piotr Czarny Janusz Piekarski Maciej Radek Małgorzata Czyż Tomasz Skorski Tomasz Śliwiński Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor Genes melanoma HDACi PARP1 valproic acid alkylating agent DNA damage |
| title | Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor |
| title_full | Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor |
| title_fullStr | Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor |
| title_full_unstemmed | Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor |
| title_short | Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor |
| title_sort | histone deacetylases hdac inhibitor valproic acid sensitizes human melanoma cells to dacarbazine and parp inhibitor |
| topic | melanoma HDACi PARP1 valproic acid alkylating agent DNA damage |
| url | https://www.mdpi.com/2073-4425/14/6/1295 |
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