title: Epigenetic reversal of acquired resistance to 5-fluorouracil treatment.
abstract: Acquired and intrinsic resistance still remains a limitation to the clinical use of 5-fluorouracil (5-FU). The contribution of epigenetic changes to the development of drug resistance remains to be elucidated. Several genes that are hypermethylated and silenced have been identified in colorectal cancer. Based on the findings described in the accompanying article, we hypothesized that acquired resistance to "pulse" 5-FU has an epigenetic origin and might be reversed. Here, we present a novel therapeutic approach to circumvent clinical resistance to bolus 5-FU, that is, treatment of bolus 5-FU-resistant colorectal cancer cells with low-dose 5-azadeoxycytidine (DAC), an inhibitor of DNA hypermethylation, restored sensitivity to 5-FU as well as 5-fluorouridine. Moreover, treatment of nude mice bearing a 5-FU-resistant tumor, characterized by decreased levels of UMP kinase (UMPK), with DAC overcame resistance to bolus 5-FU. DAC-mediated restoration of 5-FU sensitivity was associated with increases in UMPK levels. An increase in UMPK protein and mRNA levels following treatment with low-dose DAC was observed in cultured bolus 5-FU-resistant colorectal cancer cells (HCT-8) and in mice bearing these tumors. We conclude that DAC-mediated restoration of sensitivity to bolus 5-FU is mediated at least in part by increased UMPK levels and clinical resistance to 5-FU due to decreased UMPK in colorectal cancer may be overcome by including methylation inhibitors such as DAC.
authors.affiliation: Department of Medicine and Pharmacology, Robert Wood Johnson Medical School, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Humeniuk
authors.forename: Prasun J
authors.initials: PJ
authors.lastname: Mishra
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
authors.forename: Debabrata
authors.initials: D
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D057890:Epigenomics; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023061:Gene Order; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D014529:Uridine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; C001943:5-fluorouridine; D000077209:Decitabine; C023276:uridine monophosphate kinase; D009703:Nucleoside-Phosphate Kinase; D001374:Azacitidine; D005472:Fluorouracil; D014529:Uridine