title: Histone deacetylase inhibitor enhances sensitivity of non-small-cell lung cancer cells to 5-FU/S-1 via down-regulation of thymidylate synthase expression and up-regulation of p21(waf1/cip1) expression.
abstract: It is desirable to find more appropriate therapeutic opportunities in non-small-cell lung cancer (NSCLC) due to the current poor prognosis of affected patients. Recently, several histone deacetylase (HDAC) inhibitors, including suberoylanilide hydroxamic acid (SAHA), have been reported to exhibit antitumor activities against NSCLC. S-1, a novel oral fluorouracil anticancer drug, has been developed for clinical use in the treatment of NSCLC in Japan. Using an MTT assay, we analyzed the growth-inhibitory effect of 5-fluorouracil (5-FU), S-1, and SAHA against three NSCLC cell lines, as well as the breast cancer cell line MCF7 which is known to be highly sensitive to 5-FU. Combined treatment with low-dose SAHA enhanced 5-FU- and S-1-mediated cytotoxicity and resulted in synergistic effects, especially in 5-FU-resistant cells. Both the mRNA and protein expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT), which are associated with 5-FU sensitivity/response, were analyzed in the cells undergoing treatment. 5-Fluorouracil-resistant lung cancer cells displayed high expression of TS mRNA and protein. Suberoylanilide hydroxamic acid down-regulated TS mRNA and protein expression, as well as repressed the rapid induction of this factor during 5-FU treatment, in all examined cell types. We also examined the status of the Rb-E2F1 pathway, with SAHA up-regulating p21(waf1/cip1) expression via promoter histone acetylation; this, in turn, blocked the Rb-E2F1 pathway. We conclude that combination therapy with SAHA and S-1 in lung cancer may be promising due to its potential to overcome S-1 resistance via modulation of 5-FU/S-1 sensitivity-associated biomarker (TS) by HDAC inhibitor.
authors.affiliation: Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Noro
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyanaga
authors.forename: Yuji
authors.initials: Y
authors.lastname: Minegishi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okano
authors.forename: Masahiro
authors.initials: M
authors.lastname: Seike
authors.forename: Chie
authors.initials: C
authors.lastname: Soeno
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kataoka
authors.forename: Kuniko
authors.initials: K
authors.lastname: Matsuda
authors.forename: Akinobu
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D004338:Drug Combinations; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010094:Oxonic Acid / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis; D016160:Retinoblastoma Protein / Q000378:metabolism; D005641:Tegafur / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077337:Vorinostat
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004338:Drug Combinations; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; C079198:S 1 (combination); D005641:Tegafur; D000077337:Vorinostat; D010094:Oxonic Acid; D013940:Thymidylate Synthase; D005472:Fluorouracil
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