title: c-Jun-NH2-kinase-1 inhibition leads to antitumor activity in ovarian cancer.
abstract: OBJECTIVE
  To show the functional, clinical, and biological significance of c-Jun-NH(2)-kinase (JNK)-1 in ovarian carcinoma.
  
  
  METHODS
  Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of N-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.
  
  
  RESULTS
  We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. In vivo, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.
  
  
  CONCLUSIONS
  These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development.
authors.affiliation: Department of Experimental Therapeutics, Center for RNAi and non-coding-RNA, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Vivas-Mejia
authors.forename: Juliana Maria
authors.initials: JM
authors.lastname: Benito
authors.forename: Ariel
authors.initials: A
authors.lastname: Fernandez
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Lingegowda
authors.initials: L
authors.lastname: Mangala
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.forename: Arturo
authors.initials: A
authors.lastname: Chavez-Reyes
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.forename: Mark S
authors.initials: MS
authors.lastname: Carey
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Claret
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Bryan T J
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Angela
authors.initials: A
authors.lastname: Sanguino
authors.forename: Zhengong
authors.initials: Z
authors.lastname: Peng
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043925:Angiogenesis Inducing Agents; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D043925:Angiogenesis Inducing Agents; D004791:Enzyme Inhibitors; C548660:N-5-(4-(4-methylpiperazinemethyl)benzoylamido)-2-methylphenyl-4-(3-(4-methyl)pyridyl)-2-pyrimidineamine; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D048055:Mitogen-Activated Protein Kinase 8