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

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.

Class I HDAC Inhibition Leads to a Downregulation of FANCD2 and RAD51, and the Eradication of Glioblastoma Cells

“…To examine how inhibiting class I HDACs with VPA enhances sensitivity to temozolomide and BMN-673, a real-time PCR array was conducted in GMB113 and GBM114 glioblastoma cells. The aim was to monitor changes in the mRNA expression of six genes (chosen based on previous publications [ 21 , 26 ]) involved in the double-strand break repair pathway (RAD51, RAD51D, FANCD2, BRCA1, BRCA2, PALB2). In Figure 3 , the results of the PCR array showed alterations in the mRNA expression profile of RAD51 and FANCD2.…”

“…It was observed that each of the three compounds tested in this study induces apoptosis and increases the levels of phosphorylated H2A.X, thereby influencing the expression of genes involved in HR repair in glioblastoma cell lines. Other studies have shown that the tested inhibitors, PARP1 and HDAC, induced apoptosis in DMBC11, H6, and H7 cell lines by causing DNA damage [ 26 , 30 , 38 ]. Similarly, Romeo et al reported that VPA and TSA sensitized pancreatic cancer cells to an AZD2461 PARP inhibitor.…”

“…In the experiment, cells were pretreated with VPA at a concentration of 1 mmol/L for a duration of 168 h. The VPA-containing medium was refreshed every 48 h, and any remaining VPA was removed before subjecting the cells to further treatment. The treatment scheme and concentrations of the compounds used were applied in previous experiments [ 21 , 26 ]. The achieved micromolar doses in our experiments are significantly lower than those currently used in clinical practice.…”

“…In our previous studies, we demonstrated that HDAC inhibitors effectively reduce the viability of melanoma cells and may render this type of cancer more susceptible to the cytotoxic effects of DNA-damaging agents, such as dacarbazine [ 26 ]. However, whether HDAC inhibitors could sensitize LIG4-deficient glioblastoma to PARPi and TMZ remains to be investigated.…”

Deacetylation of Histones and Non-histone Proteins in Inflammatory Diseases and Cancer Therapeutic Potential of Histone Deacetylase Inhibitors

“…For instance, the class I HDAC inhibitor valproic acid has been shown to enhance the effectiveness of chemotherapy agents in human melanoma cells [ 106 ]. Similarly, the class I HDAC inhibitor domatinostat has been shown to sensitize pancreatic cancer cells to chemotherapy by exerting its effect on the transcription factor FOXM1 [ 107 ]. Likewise, the potential of HDAC inhibitors to overcome immunotherapy resistance has been revealed [ 108 ].…”