title: Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat.
abstract: To investigate and elucidate the mechanism for the potentiation of cisplatin anticancer activity by belinostat in platinum (Pt)-resistant lung cancer cells.
  
  
  
  Combination of cisplatin and belinostat was investigated in two pairs of parental and cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines. The Pt-resistant cell models exhibited overexpression of the efflux transporter ABCC2 and enhanced DNA repair capacity. Cellular accumulation of cisplatin and extent of DNA platination were measured by inductively coupled plasma optical emission spectrometer. Expression of Pt transporters and DNA repair gene were determined by quantitative real-time PCR. Inhibition of ABCC2 transport activity was examined by flow cytometric assay. Regulation of ABCC2 at the promoter level was studied by chromatin immunoprecipitation assay.
  
  
  
  In Pt-resistant lung cancer cells, belinostat apparently circumvent the resistance through inhibition of both ABCC2 and DNA repair-mediated mechanisms. The combination of belinostat and cisplatin were found to display synergistic cytotoxic effect in cisplatin-resistant lung cancer cell lines when the two drugs were added concomitantly or when belinostat was given before cisplatin. Upon the concomitant administration of belinostat, cellular accumulation of cisplatin and formation of DNA-Pt adducts were found to be increased whereas expression levels of the efflux transporter ABCC2 and the DNA repair gene ERCC1 were inhibited in Pt-resistant cells. Belinostat-mediated downregulation of ABCC2 was associated with an increase association of a transcriptional repressor (negative cofactor 2) but reduced association of a transcriptional activator (TFIIB) to the ABCC2 promoter. The data advocates the use of belinostat as a novel drug resistance reversal agent for use in combination cancer chemotherapeutic regimens.
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: kennethto@cuhk.edu.hk.
authors.forename: Kenneth Kin-Wah
authors.initials: KK
authors.lastname: To
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Wing-Sum
authors.initials: WS
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China.
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000235:genetics; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics; D010984:Platinum / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D035581:Transcription Factor TFIIB / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D018736:DNA Adducts; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010750:Phosphoproteins; D010984:Platinum; D013449:Sulfonamides; D035581:Transcription Factor TFIIB; D014157:Transcription Factors; C000715087:ABCC2 protein, human; C075995:down-regulator of transcription 1; C487081:belinostat
keywords: Belinostat; DNA repair; Drug resistance; Efflux transporters; Platinum anticancer drug