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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.

SUBMITTER: Kalal BS

PROVIDER: S-EPMC6473314 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Kalal Bhuvanesh Sukhlal BS Pai Vinitha Ramanath VR Behera Santosh Kumar SK Somashekarappa Hiriyur Mallaiah HM

Medical sciences (Basel, Switzerland) 20190322 3

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 ...[more]

PMID: 30909413

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Project description:IntroductionPersistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive.MethodsThe cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection.ResultsIn this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes.ConclusionHDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.

Project description:Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through its action as a histone deacetylase inhibitor. CD133 is considered to be a cancer stem cell marker in several tumors including neuroblastoma. CD133 transcription is strictly regulated by epigenetic modifications. We evaluated the epigenetic effects of treatment with 1mM VPA and its influence on the expression of CD133 in four human neuroblastoma cell lines. Chemoresistance and cell cycle of CD133+ and CD133- populations were examined by flow cytometry. We performed bisulfite conversion followed by methylation-sensitive high resolution melting analysis to assess the methylation status of CD133 promoters P1 and P3. Our results revealed that VPA induced CD133 expression that was associated with increased acetylation of histones H3 and H4. On treatment with VPA and cytostatics, CD133+ cells were mainly detected in the S and G2/M phases of the cell cycle and they showed less activated caspase-3 compared to CD133- cells. UKF-NB-3 neuroblastoma cells which express CD133 displayed higher colony and neurosphere formation capacities when treated with VPA, unlike IMR-32 which lacks for CD133 protein. Induction of CD133 in UKF-NB-3 was associated with increased expression of phosphorylated Akt and pluripotency transcription factors Nanog, Oct-4 and Sox2. VPA did not induce CD133 expression in cell lines with methylated P1 and P3 promoters, where the CD133 protein was not detected. Applying the demethylating agent 5-aza-2'-deoxycytidine to the cell lines with methylated promoters resulted in CD133 re-expression that was associated with a drop in P1 and P3 methylation level. In conclusion, CD133 expression in neuroblastoma can be regulated by histone acetylation and/or methylation of its CpG promoters. VPA can induce CD133+ cells which display high proliferation potential and low sensitivity to cytostatics in neuroblastoma. These results give new insight into the possible limitations to use VPA in cancer therapy.

Dataset Information

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

Publications

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

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