c-Jun-NH2-kinase-1 inhibition leads to antitumor activity in ovarian cancer.
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.
Vivas-Mejia
Pablo
P
Department of Experimental Therapeutics, Center for RNAi and non-coding-RNA, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Benito
Juliana Maria
JM
Fernandez
Ariel
A
Han
Hee-Dong
HD
Mangala
Lingegowda
L
Rodriguez-Aguayo
Cristian
C
Chavez-Reyes
Arturo
A
Lin
Yvonne G
YG
Carey
Mark S
MS
Nick
Alpa M
AM
Stone
Rebecca L
RL
Kim
Hye Sun
HS
Claret
Francois-Xavier
FX
Bornmann
William
W
Hennessy
Bryan T J
BT
Sanguino
Angela
A
Peng
Zhengong
Z
Sood
Anil K
AK
Lopez-Berestein
Gabriel
G
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
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