2. Academic Validation
  3. Histone Deacetylases (HDAC) Inhibitor-Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor

Histone Deacetylases (HDAC) Inhibitor-Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor

  • Genes (Basel). 2023 Jun 20;14(6):1295. doi: 10.3390/genes14061295.
Małgorzata Drzewiecka 1,  Anna Gajos-Michniewicz 2,  Grażyna Hoser 3,  Dominika Jaśniak 1,  Gabriela Barszczewska-Pietraszek 1,  Przemysław Sitarek 4,  Piotr Czarny 5,  Janusz Piekarski 6,  Maciej Radek 7,  Małgorzata Czyż 2,  Tomasz Skorski 8,  Tomasz Śliwiński 1
Affiliations

Affiliations

  • 1 Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland.
  • 2 Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland.
  • 3 Department of Flow Cytometry, Medical Center for Postgraduate Education, 01-813 Warsaw, Poland.
  • 4 Department of Medical Biology, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland.
  • 5 Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland.
  • 6 Department of Surgical Oncology, Medical University of Lodz, 90-419 Lodz, Poland.
  • 7 Department of Neurosurgery, Surgery of Spine and Peripheral Nerves, Medical University of Lodz, University Hospital WAM-CSW, 90-549 Lodz, Poland.
  • 8 Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
PMID: 37372475 DOI: 10.3390/genes14061295
Abstract

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.

Keywords

DNA damage; HDACi; PARP1; alkylating agent; melanoma; valproic acid.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16106
    99.89%, PARP Inhibitor