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Open AccessArticle

HDAC2 Inhibitor Valproic Acid Increases Radiation Sensitivity of Drug-Resistant Melanoma Cells

1
Department of Biochemistry, Yenepoya Medical College, Yenepoya (Deemed to be University), Mangaluru-575018, Karnataka, India
2
Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangaluru-575018, Karnataka, India
3
Centre for Application of Radioisotopes and Radiation Technology, Mangalore University, Mangaluru-574199, Karnataka, India
*
Author to whom correspondence should be addressed.
Med. Sci. 2019, 7(3), 51; https://doi.org/10.3390/medsci7030051
Received: 18 December 2018 / Revised: 15 March 2019 / Accepted: 18 March 2019 / Published: 22 March 2019
(This article belongs to the Section Cancer and Cancer-Related Research)
Resistance to anticancer drugs limits the effectiveness of chemotherapy in cancers. Melanoma cell lines B16F10C and A375C (parental) and B16F10R and A375R (drug-resistant sublines) were used to test radiation sensitization potential of valproic acid (VPA), an inhibitor of Histone deacetylase2 (HDAC2) and LDN193189 (BMP inhibitor). Inhibitors of other signaling pathways were tested for cross-resistance with the resistant cell lines. Cells were pretreated with low concentrations of VPA/ LDN193189 and exposed to 2 Gy radiation for radiation sensitization experiments. Assays-3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), live/dead, clonogenic, and melanin estimation were performed to test the effects of radiation sensitization. Interactions of VPA and HDAC2 were studied in silico. Dose-dependent growth inhibition was observed with all tested drugs. Radiation sensitization of melanoma cells with low dose of VPA induced synergistic cell death, decreased clonogenicity, and decreased melanin content. In silico docking showed two stable interactions between Arg39 of HDAC2 and VPA. In conclusion, pretreatment with low doses of VPA has a potential for sensitizing melanoma cells to low doses of radiation. The binding of VPA to HDAC2 reverses the drug resistance in melanoma and induces the cell death. Sensitization effects of VPA can be used for targeting drug-resistant cancers. View Full-Text
Keywords: cytotoxic; drug-resistance; histone deacetylase 2; melanoma; radiosensitizer; valproic acid cytotoxic; drug-resistance; histone deacetylase 2; melanoma; radiosensitizer; valproic acid
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Kalal, B.S.; Pai, V.R.; Behera, S.K.; Somashekarappa, H.M. HDAC2 Inhibitor Valproic Acid Increases Radiation Sensitivity of Drug-Resistant Melanoma Cells. Med. Sci. 2019, 7, 51.

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