Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells.

Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE

Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.

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; 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

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.

Cold Spring Harb Symp Quant Biol. 2007;72:623-36. (PMID: 18419322)
J Clin Oncol. 2004 Feb 1;22(3):517-28. (PMID: 14752075)
PLoS One. 2011;6(11):e26740. (PMID: 22069467)
J Lab Clin Med. 1998 Jul;132(1):6-8. (PMID: 9665365)
Cell Stem Cell. 2009 Mar 6;4(3):191-2. (PMID: 19265652)
J Natl Cancer Inst. 2007 Sep 19;99(18):1410-4. (PMID: 17848677)
Br J Cancer. 2012 Mar 27;106(7):1288-96. (PMID: 22382690)
J Pineal Res. 1993 Jan;14(1):27-33. (PMID: 8483104)
Cancer Res. 1981 Nov;41(11 Pt 1):4432-6. (PMID: 6796259)
Neuroscience. 2008 Jun 23;154(2):541-50. (PMID: 18462887)
Free Radic Res. 2011 Nov;45(11-12):1333-41. (PMID: 21923620)
Cancer Res. 2004 Oct 1;64(19):7011-21. (PMID: 15466194)
Mol Cell Biol. 2006 Nov;26(22):8572-85. (PMID: 16954373)
Cancer Lett. 2010 Jan 28;287(2):216-23. (PMID: 19632770)
J Res Med Sci. 2010 Jul;15(4):225-8. (PMID: 21526086)
Toxicology. 2010 Nov 28;278(1):55-67. (PMID: 20417677)
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):787-91. (PMID: 8290600)
Gene. 2012 Jul 15;503(1):1-11. (PMID: 22569208)
Nat Rev Cancer. 2002 Jan;2(1):48-58. (PMID: 11902585)
Cancer Invest. 1987;5(4):379-85. (PMID: 3311315)
Cell Cycle. 2009 Sep 15;8(18):2936-44. (PMID: 19713741)
Nature. 2004 Nov 18;432(7015):396-401. (PMID: 15549107)
J Pharm Pharmacol. 2002 Oct;54(10):1299-321. (PMID: 12396291)
Cancer Res. 2006 Jan 15;66(2):1081-8. (PMID: 16424044)
Expert Rev Neurother. 2009 Oct;9(10):1447-9. (PMID: 19831832)
J Pineal Res. 1993 Jan;14(1):1-10. (PMID: 8483103)
Curr Med Chem. 2012;19(22):3805-21. (PMID: 22612707)

0 (ABCG2 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
0 (ATP-Binding Cassette Transporters)
0 (Antineoplastic Agents)
0 (Neoplasm Proteins)
JL5DK93RCL (Melatonin)

Date Created: 20130502 Date Completed: 20130726 Latest Revision: 20211021

20250114

PMC3670480

10.1038/bjc.2013.188

23632480