1. Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells.
- Author
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Martín V, Sanchez-Sanchez AM, Herrera F, Gomez-Manzano C, Fueyo J, Alvarez-Vega MA, Antolín I, and Rodriguez C
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters metabolism, ATP-Binding Cassette Transporters physiology, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Brain drug effects, Brain metabolism, Brain pathology, Brain Neoplasms genetics, Cell Line, Tumor, DNA Methylation physiology, Drug Evaluation, Preclinical, Drug Resistance, Multiple genetics, Drug Resistance, Neoplasm genetics, Drug Synergism, Gene Expression Regulation, Neoplastic drug effects, Glioblastoma genetics, Humans, Melatonin administration & dosage, Neoplasm Proteins metabolism, Neoplasm Proteins physiology, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Neoplastic Stem Cells physiology, Promoter Regions, Genetic drug effects, ATP-Binding Cassette Transporters genetics, Brain Neoplasms pathology, DNA Methylation drug effects, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Glioblastoma pathology, Melatonin pharmacology, Neoplasm Proteins genetics, Neoplastic Stem Cells drug effects
- Abstract
Background: Current evidence indicates that a stem cell-like sub-population within malignant glioblastomas, that overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters, is responsible for multidrug resistance and tumour relapse. Eradication of the brain tumour stem cell (BTSC) compartment is therefore essential to achieve a stable and long-lasting remission., Methods: Melatonin actions were analysed by viability cell assays, flow cytometry, quantitative PCR for mRNA expression, western blot for protein expression and quantitative and qualitative promoter methylation methods., Results: Combinations of melatonin and chemotherapeutic drugs (including temozolomide, current treatment for malignant gliomas) have a synergistic toxic effect on BTSCs and A172 malignant glioma cells. This effect is correlated with a downregulation of the expression and function of the ABC transporter ABCG2/BCRP. Melatonin increased the methylation levels of the ABCG2/BCRP promoter and the effects on ABCG2/BCRP expression and function were prevented by preincubation with a DNA methyltransferase inhibitor., Conclusion: Our results point out a possible relationship between the downregulation of ABCG2/BCRP function and the synergistic toxic effect of melatonin and chemotherapeutic drugs. Melatonin could be a promising candidate to overcome multidrug resistance in the treatment of glioblastomas, and thus improve the efficiency of current therapies.
- Published
- 2013
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