title: Demethylation restores SN38 sensitivity in cells with acquired resistance             to SN38 derived from human cervical squamous cancer cells.
abstract: Using seven monoclonal SN38-resistant subclones established from ME180 human             cervical squamous cell carcinoma cells, we examined the demethylation effects             of 5-aza-2'-deoxycytidine (5-aza-CdR) on the SN38-sensitivity of the cells as             well as the expression of death-associated protein kinase (DAPK) in the SN38-resistant             cells. The DAPK expression levels were evaluated among parent ME180 cells, SN38-resistant             ME180 cells and cisplatin-resistant ME180 cells by methylation-specific DAPK-PCR,             quantitative RT-PCR and western blot analysis. The SN38-resistant cells co-treated             with SN38 and 5-aza-CdR strongly exhibited enhanced SN38-sensitivities resembling             those found in the parent cells. In the SN38-resistant subclones, no relationships             were found between the restored SN38 sensitivity and hypermethylation of the DAPK             promoter, DAPK mRNA expression, DAPK protein expression and induction of DAPK             protein after 5-aza-CdR treatment, unlike the strong suppression of 5-aza-CdR-induced             DAPK protein expression in the cisplatin-resistant subclones. These findings indicate             that reversibly methylated molecules, but not DAPK, may regulate SN38 resistance,             and that demethylating agents can be strong sensitizing anticancer chemotherapeutic             drugs for SN38-resistant cancers.
authors.affiliation: Santamaria Hospital, 13-15 Shinjo-cho, Ibaraki, Osaka 567-0884,                     Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.forename: Saori
authors.initials: S
authors.lastname: Toujima
authors.forename: Tomoko
authors.initials: T
authors.lastname: Utsunomiya
authors.forename: Toshihide
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Aya
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Madoka
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sasaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanizaki
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Junko
authors.initials: J
authors.lastname: Tanaka
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yukawa
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003640:Dealkylation; D064550:Death-Associated Protein Kinases; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D000077146:Irinotecan; D000077209:Decitabine; D015254:DNA Modification Methylases; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D001374:Azacitidine; D002945:Cisplatin; D002166:Camptothecin