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

Abstract

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.

Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma

“…Valproic acid (VPA), an inhibitor of HDACs, binds to HDAC2 and enhances sensitivity to anti-cancer drugs (Kalal et al, 2019). HDAC2 binds to the cancer/testis antigens, such as CAGE, and leads to multi-drug resistance by decreasing p53 expression in melanoma cells (Kim et al, 2010, Figure 3A).…”

Studies on imidazo[2,1-b][1,3]benzothiazole derivatives as new radiosensitizers

“…The anticancer activity screening of compounds 3a-h was performed in HepG2 cell line, two parental melanoma cell line (human melanoma cell line, A375C and mouse melanoma cell line, A375C) and two drug resistant sublines (B16F10R and A375R) [10]. Cells cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum, 2 mmol/l glutamine, 1% antibiotics solution (100 U/ml penicillin G and 100 mg/ml streptomycin).…”

Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

“…The anticancer effect of HDAC inhibitors could be further potentiated by development of dual mode, chimeric inhibitors [ 58 ] or by application of combined therapy together with other antitumour agents with a different mode of action such as epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor [ 59 ], cisplatin, a metalating agent [ 60 ], gemcitabine interfering nucleic acid synthesis [ 61 ], decitabine, a hypomethylating agent inhibiting DNA methyltransferase [ 62 ], doxorubicin [ 63 ] and ellipticin [ 64 ] DNA intercalators and topoisomerase II inhibitors, Temozolomide, an alkylating agent [ 65 ], proteasome inhibitors [ 66 ], BET (bromodomain and extraterminal domain proteins) inhibitors [ 67 ], and RG7388, an inhibitor of tumour-associated protein MDM2 [ 68 ]. The antitumour effect of HDAC inhibitors was also combined with photodynamic therapy [ 69 ], radiation therapy (increasing radiation sensitivity) [ 70 , 71 , 72 ] and the application of oncolytic viruses [ 73 , 74 ].…”