title: Effects and mechanisms of the combination of suberoylanilide hydroxamic acid and bortezomib on the anticancer property of gemcitabine in pancreatic cancer.
abstract: OBJECTIVE
  Earlier studies that dealt with the combination therapy of gemcitabine and histone deacetylation inhibitors for pancreatic cancer revealed unsatisfactory results. The activation of nuclear factor κB (NF-κB) was referred as one of the attributable causes, and we attempted to overcome this resistance by the addition of a proteasome inhibitor.
  
  
  METHODS
  The influences of suberoylanilide hydroxamic acid (vorinostat, SAHA), a histone deacetylase inhibitor, and bortezomib, a novel selective antagonist of 26S proteasome, with or without gemcitabine on cell growth and apoptosis and the expressions of related proteins were observed in pancreatic cancer cell lines (MiaPaCa-2 and ASPC-1). The xenograft model of pancreatic cancer was used to notice effects in vivo.
  
  
  RESULTS
  Vorinostat and bortezomib had independent inhibitory effects and potentiated the antitumor property of gemcitabine in vitro. In the xenograft model, more augmented effects were achieved when bortezomib was combined with gemcitabine than gemcitabine alone. The down-regulation of pAkt and suppression of NF-κB activity was induced by the triple combination.
  
  
  CONCLUSIONS
  The triple combination of vorinostat, bortezomib, and gemcitabine resulted in the strongest antitumor effects both in vitro and in vivo and pAkt and NF-κB seems to be involved in this process.
authors.affiliation: Department of Internal Medicine, Dongguk University Ilsan Hospital, Graduate School of Medicine, Dongguk University, Seoul, Republic of Korea.
authors.forename: Jun Kyu
authors.initials: JK
authors.lastname: Lee
authors.forename: Ji Kon
authors.initials: JK
authors.lastname: Ryu
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Yang
authors.forename: Sang Myung
authors.initials: SM
authors.lastname: Woo
authors.forename: Joo Kyung
authors.initials: JK
authors.lastname: Park
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Yoon
authors.forename: Sang Hyub
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyoung-Sin
authors.initials: KS
authors.lastname: Jeong
authors.forename: Yong-Tae
authors.initials: YT
authors.lastname: Kim
authors.forename: Yong Bum
authors.initials: YB
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000008:administration & dosage; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D003841:Deoxycytidine; D000077337:Vorinostat; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000093542:Gemcitabine