Inhibition of tumor growth, angiogenesis, and tumor cell proliferation by a small molecule inhibitor of c-Jun N-terminal kinase.
c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family, and its function is critical for signal transduction in tumor and endothelial cells. JNK is a serine/threonine protein kinase that phosphorylates c-Jun, a component of the activator protein-1 transcription factor complex. We hypothesize that inhibiting JNK will lead to the inhibition of tumor growth; therefore, we evaluated the efficacy of the recently described JNK inhibitor SP600125 [anthra[1,9-cd] pyrazol-6 (2H)-one]. SP600125 is an anthrapyrazole that is a reversible, ATP-competitive inhibitor of JNK1/2. SP600125 exhibited broad-based antiproliferative activity in human endothelial and tumor cell lines. SP600125 affects proliferation by arresting cells in the G2/M phase of the cell cycle. SP600125 also acts to inhibit endothelial cell migration. In cell lines, a correlation of cell growth inhibition with reduced JNK activity was observed. The systemic administration of SP600125 resulted in the inhibition of DU145 human prostate carcinoma xenografts and murine Lewis lung carcinoma. SP600125 also enhanced the potency of cyclophosphamide in the inhibition of Lewis lung tumor growth. These data indicate the therapeutic antitumor potential of small molecule inhibitors that act to block the cellular activity of JNK.
Ennis
Bruce W
BW
Celgene Corporation, 4550 Towne Centre Court, San Diego, CA 92121, USA.
Fultz
Kimberly E
KE
Smith
Kent A
KA
Westwick
John K
JK
Zhu
Dan
D
Boluro-Ajayi
Michael
M
Bilter
Graham K
GK
Stein
Bernd
B
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*
D020533:Angiogenesis Inhibitors; D000873:Anthracenes; D000970:Antineoplastic Agents; C432165:pyrazolanthrone