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褪黑素诱导 ABCG2/BCRP 启动子甲基化作为克服脑肿瘤干细胞多药耐药的新机制。

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

机构信息

Departamento de Morfología y Biología Celular, Facultad de Medicina, C/Julian Claveria 6, 33006 Oviedo, Spain.

出版信息

Br J Cancer. 2013 May 28;108(10):2005-12. doi: 10.1038/bjc.2013.188. Epub 2013 Apr 30.

DOI:10.1038/bjc.2013.188
PMID:23632480
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3670480/
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.

摘要

背景

目前的证据表明，恶性神经胶质瘤中存在一个具有干细胞样特性的亚群，其过度表达三磷酸腺苷结合盒（ABC）家族转运蛋白的成员，是多药耐药和肿瘤复发的原因。因此，消除脑肿瘤干细胞（BTSC）是实现稳定和持久缓解的关键。

方法

通过细胞活力测定、流式细胞术、mRNA 表达的定量 PCR、蛋白表达的 Western blot 以及定量和定性启动子甲基化方法分析褪黑素的作用。

结果

褪黑素与化疗药物（包括替莫唑胺，目前用于治疗恶性神经胶质瘤）的联合对 BTSC 和 A172 恶性神经胶质瘤细胞具有协同的毒性作用。这种作用与 ABC 转运蛋白 ABCG2/BCRP 的表达和功能下调相关。褪黑素增加了 ABCG2/BCRP 启动子的甲基化水平，而 DNA 甲基转移酶抑制剂的预孵育则阻止了对 ABCG2/BCRP 表达和功能的影响。

结论

我们的结果指出，褪黑素和化疗药物的协同毒性作用与 ABCG2/BCRP 功能的下调之间可能存在关联。褪黑素可能是一种有前途的候选药物，可用于克服治疗神经胶质瘤中的多药耐药性，从而提高现有治疗方法的效率。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/594562b5c57b/bjc2013188f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/db802c8536c0/bjc2013188f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/92ff7cfe10dd/bjc2013188f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/9a15b5a3497c/bjc2013188f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/594562b5c57b/bjc2013188f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/db802c8536c0/bjc2013188f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/92ff7cfe10dd/bjc2013188f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/9a15b5a3497c/bjc2013188f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebf8/3670480/594562b5c57b/bjc2013188f4.jpg

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