Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo

Title: Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo
Authors: Steele, N
Finn, P
Brown, R
Plumb, JA
Item Type: Journal Article
Abstract: Histone deacetylation and DNA methylation have a central role in the control of gene expression in tumours, including transcriptional repression of tumour suppressor genes and genes involved in sensitivity to chemotherapy. Treatment of cisplatin-resistant cell lines with an inhibitor of DNA methyltransferases, 2-deoxy-5′azacytidine (decitabine), results in partial reversal of DNA methylation, re-expression of epigenetically silenced genes including hMLH1 and sensitisation to cisplatin both in vitro and in vivo. We have investigated whether the combination of decitabine and a clinically relevant inhibitor of histone deacetylase activity (belinostat, PXD101) can further increase the re-expression of genes epigenetically silenced by DNA methylation and enhance chemo-sensitisation in vivo at well-tolerated doses. The cisplatin-resistant human ovarian cell line A2780/cp70 has the hMLH1 gene methylated and is resistant to cisplatin both in vitro and when grown as a xenograft in mice. Treatment of A2780/cp70 with decitabine and belinostat results in a marked increase in expression of epigenetically silenced MLH1 and MAGE-A1 both in vitro and in vivo when compared with decitabine alone. The combination greatly enhanced the effects of decitabine alone on the cisplatin sensitivity of xenografts. As the dose of decitabine that can be given to patients and hence the maximum pharmacodynamic effect as a demethylating agent is limited by toxicity and eventual re-methylation of genes, we suggest that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumours that have acquired drug resistance due to DNA methylation and gene silencing.
Issue Date: 3-Mar-2009
Date of Acceptance: 15-Jan-2009
URI: http://hdl.handle.net/10044/1/57169
DOI: https://dx.doi.org/10.1038/sj.bjc.6604932
ISSN: 0007-0920
Publisher: Cancer Research UK
Start Page: 758
End Page: 763
Journal / Book Title: British Journal of Cancer
Volume: 100
Issue: 5
Copyright Statement: Publisher's version/PDF may be used after 12 months embargo, under a Creative Commons Attribution Non-Commercial Share Alike License
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
DNA methylation
MLH1
drug sensitivity
decitabine
histone deacetylase inhibitor
HUMAN TUMOR XENOGRAFTS
OVARIAN-CANCER
DEACETYLASE INHIBITION
RESISTANCE
5-AZA-2'-DEOXYCYTIDINE
DEMETHYLATION
CHEMOTHERAPY
EXPRESSION
PROMOTER
Acetylation
Adaptor Proteins, Signal Transducing
Animals
Antigens, Neoplasm
Antineoplastic Combined Chemotherapy Protocols
Azacitidine
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
Drug Resistance, Neoplasm
Enzyme Inhibitors
Female
Gene Expression Regulation, Neoplastic
Histone Acetyltransferases
Humans
Hydroxamic Acids
Melanoma-Specific Antigens
Mice
Mice, Nude
MutL Protein Homolog 1
Neoplasm Proteins
Nuclear Proteins
Ovarian Neoplasms
Sulfonamides
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
DNA (Cytosine-5-)-Methyltransferase
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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