Inhibition of Tumor Growth, Angiogenesis, and Tumor Cell Proliferation by a Small Molecule Inhibitor of c-Jun N-terminal Kinase

Abstract

c-Jun N-terminal kinase (JNK) is a member of the mitogenactivated 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 G 2 /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.

c-Jun NH2 Terminal Kinase Activation and Decreased Expression of Mitogen-Activated Protein Kinase Phosphatase-1 Play Important Roles in Invasion and Angiogenesis of Urothelial Carcinomas

“…Whatever the case, it should be emphasized that activated JNK has positive and negative effects on urothelial carcinoma development. As to the role of JNK in tumor angiogenesis, Kim and colleagues 53 reported thrombospondin production can be mediated through JNK activation, whereas Ennis and colleagues 54 found JNK inhibition to suppress endothelial cell migration and development of vasculature.…”

Targeting c-Jun and JunB proteins as potential anticancer cell therapy

“…It has been previously reported that the JNK inhibitor cause tumor regression in vivo (Ennis et al, 2005;Gururajan et al, 2005), we therefore assessed the combined anti-JunB/c-Jun strategy against melanoma cells in the C57BL/6 mice strain using conditions where the SP treatment alone had no significant effect. We observed a striking decrease in tumor size, apoptosis induction and a significant increase in the survival of mice inoculated with the JunB knockdown cells after the SP administration, demonstrating the enhanced potential therapeutics in vivo of the JNK inhibitor in cells lacking JunB.…”

“…This drug acts as a reversible ATP-competitive inhibitor of JNK, and has been shown to exhibit a selectivity of >20-fold relative to other tested kinases. Recent data show that SP inhibits cancer cell proliferation and tumor growth in mice (Ennis et al, 2005). Since increased c-Jun levels were associated with human melanomas (Choi et al, 2005;Lopez-Bergami et al, 2007) and based upon the fibroblast results described above, we reasoned that the effects of targeting c-Jun using SP in the melanoma-derived cell c-Jun/JunB inactivation induces apoptosis in cancer cells EN Gurzov et al line B16-F10 could be enhanced by additional silencing of JunB.…”

MKK signaling and vascularization

“…Whereas MEK1/2 inhibitors prevent VEGF-induced cell proliferation (Rousseau et al, 1997;Pedram et al, 1998), p38 MAPK inhibitors reportedly prevent VEGF-induced cytoskeletal re-organization and cell migration (Rousseau et al, 1997). The JNK pathway has also been linked to in vitro endothelial cell motility (Shin et al, 2001;Ennis et al, 2005) and proliferation (Ennis et al, 2005).…”