Valproic Acid Enhances Radiosensitization via DNA Double-strand Breaks for Boronophenylalanine-mediated Neutron Capture Therapy in Melanoma Cells

Abstract

Background: Boron neutron capture therapy (BNCT) is a radiotherapeutic approach that can destroy cancer cells while sparing the surrounding normal cells. Currently, boronophenylalanine (BPA) is the most common boron delivery agent used in BNCT for treating recurrent cancers of the head and neck, gliomas, and melanomas. On the other hand, valproic acid (VPA) is one of the representative class I histone deacetylase inhibitors (HDACi), which is a promising sensitizer for cancer therapies. In this study, we aimed to verify whether VPA could induce an enhanced effect in destroying melanoma cells in concurrence with BNCT and to explore the underlying mechanism of VPA-BNCT action in killing these cells.

Materials and methods: Murine melanoma B16-F10 cells were pre-treated with VPA and irradiated with neutron during BPA-BNCT. We explored the clonogenic assay and the expression of phosphorylated H2AX (γH2AX) for cell survival and DNA double-strand breaks (DSBs), respectively. We also examined the expression levels of DNA damage responses-associated proteins and performed a cell cycle analysis.

Results: Our data indicated that the combination treatment of VPA and BNCT could significantly inhibit the growth of melanoma cells. Furthermore, VPA-BNCT treatment could exacerbate and perturb DNA DSBs in B16-F10 cells. In addition, pre-treatment of VPA abolished the G₂/M arrest checkpoint caused by BNCT.

Conclusion: Our results demonstrate that VPA has the potential to serve as a radiosensitizer of BPA-mediated BNCT for melanoma. These findings could improve BNCT treatments for melanoma.

Keywords: Boron neutron capture therapy; DNA double-strand breaks; combination treatment; histone deacetylase inhibitors; melanoma.