title: Different effects of epigenetic modifiers on the cytotoxicity induced by 5-fluorouracil, irinotecan or oxaliplatin in colon cancer cells.
abstract: We investigated the effects of epigenetic modifiers such as DNA methyltransferase (DNMT) or histone deacetylase (HDAC) inhibitors on the cytotoxicity induced by 3 anticancer drugs (5-fluorouracil (5-FU), irinotecan (CPT-11) or its active form SN38, and oxaliplatin (L-OHP)) in human colorectal cancer (CRC) cells. Cytotoxicity in 4 CRC cell lines (HT29, SW480, SW48 and HCT116) was examined by colorimetric assay after drug treatment for 72 h. The effects of drug combinations were analyzed by an isobologram method. SW480 cells showed the lowest sensitivity to cytotoxicity induced by the anticancer drugs among the 4 CRC cell lines. In SW480 cells, DNMT inhibitors, such as decitabine (DAC), azacytidine and zebularine (Zeb), showed synergic effects on the cytotoxicity induced by anticancer drugs except for SN-38 plus Zeb, while HDAC inhibitors, trichostatin A, suberoylanilide hydroxamic acid and valproic acid, showed antagonistic effects. DAC showed the most potent synergic effects among the epigenetic modifiers studied. Thus, we examined whether the synergic effect of DAC is observed in other different CRC cell lines, HT29, SW48 and HCT116 cells. In all 4 CRC cell lines, the cytotoxicity of L-OHP was enhanced in a synergic manner by co-treatment with DAC. However, synergic effects of DAC with 5-FU or CPT-11 (SN-38) were not observed in 4 CRC cell lines.
authors.affiliation: Department of Pharmaceutics, Kobe Pharmaceutical University.
authors.forename: Mika
authors.initials: M
authors.lastname: Ikehata
authors.forename: Mao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Yamada
authors.forename: Shota
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ueda
authors.forename: Seigo
authors.initials: S
authors.lastname: Iwakawa
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004247:DNA / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D005472:Fluorouracil / Q000627:therapeutic use*; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D000077209:Decitabine; D004247:DNA; D015254:DNA Modification Methylases; D001374:Azacitidine; D005472:Fluorouracil; D002166:Camptothecin