Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo.
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.
Steele
N
N
Centre for Oncology and Applied Pharmacology, University of Glasgow, UK.
Finn
P
P
Brown
R
R
Plumb
J A
JA
D000107:Acetylation / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D058950:Melanoma-Specific Antigens; D051379:Mice; D008819:Mice, Nude; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C501486:MLH1 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D013449:Sulfonamides; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D051548:Histone Acetyltransferases; D000070957:MutL Protein Homolog 1; C487081:belinostat; D001374:Azacitidine