RESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina/análogos & derivados , Camptotecina/análogos & derivados , Neoplasias del Colon/tratamiento farmacológico , Epigénesis Genética , Fluorouracilo/uso terapéutico , Compuestos Organoplatinos/uso terapéutico , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Azacitidina/farmacología , Azacitidina/uso terapéutico , Camptotecina/uso terapéutico , Línea Celular Tumoral , Neoplasias del Colon/genética , ADN/efectos de los fármacos , Metilasas de Modificación del ADN/antagonistas & inhibidores , Decitabina , Sinergismo Farmacológico , Células HCT116 , Células HT29 , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Irinotecán , OxaliplatinoRESUMEN
The discovery of small and potent peptide antagonists of the corticotropin-releasing factor (CRF) receptor is described. Through the structure-activity relationship studies of 12-amino acid peptide corresponding to the C-terminal residues of astressin, we assumed that a particular surface of the alpha-helix was important for binding to the receptor. The small peptide containing d-Ala31 and cyclohexylalanine38 on that surface was as potent as astressin in binding to the CRF receptor and showed significant ACTH suppression when administered to rats.