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.