title: Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells.
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.
  
  
  CONCLUSIONS
  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.
authors: Departamento de Morfología y Biología Celular, Facultad de Medicina, C/Julian Claveria 6, 33006 Oviedo, Spain. martinvanesa@uniovi.es
authors: V
authors: V
authors: Martín
authors: A M
authors: AM
authors: Sanchez-Sanchez
authors: F
authors: F
authors: Herrera
authors: C
authors: C
authors: Gomez-Manzano
authors: J
authors: J
authors: Fueyo
authors: M A
authors: MA
authors: Alvarez-Vega
authors: I
authors: I
authors: Antolín
authors: C
authors: C
authors: Rodriguez
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008550:Melatonin / Q000008:administration & dosage / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D008550:Melatonin
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