Antiangiogenic effects of a protein kinase Cbeta-selective small molecule.

Background: Protein kinase C frequently plays a central role in the intracellular signal transduction of growth factors and cytokines.

Methods: The acyclic bisindolylmaleimide 317615 x 2HCl was identified as a potent selective inhibitor of protein kinase Cbeta. The compound 317615 x 2HCl was tested in culture and in vivo in the rat corneal micropocket and in the SW2 small-cell lung carcinoma human tumor xenograft.

Results: In cell culture, 317615 x 2HCl was a more potent inhibitor of VEGF-stimulated HUVEC proliferation (IC50 150 nM, 72 h) than of human SW2 small-cell lung carcinoma cell proliferation (IC50 3.5 microM, 72 h). When administered orally twice daily for 10 days, the compound 317615 x 2HCl markedly decreased the neoangiogenesis induced by VEGF or bFGF in the rat corneal micropocket assay. To assess antitumor efficacy, 317615 x 2HCl was administered orally twice daily to nude mice bearing SW2 xenograft tumors on days 14 through 30 after tumor implantation. The number of countable intratumoral vessels was decreased in a dose-dependent manner reaching as low as one-quarter the number in the control tumors. The decrease in intratumoral vessels was paralleled by increases in tumor growth delay. Treatment of the tumor-bearing animals with paclitaxel or carboplatin followed by treatment with 317615 x 2HCl resulted in a 2.5- to 3.0-fold increase in tumor growth delay compared with the standard chemotherapeutic agents alone.

Conclusions: 317615 x 2HCl represents a new approach to antiangiogenic therapy in cancer-blocking multiple growth factor signaling pathways in endothelial cells with a single agent. 317615 x HCl is in early clinical testing.