Antiangiogenic effects of a protein kinase Cbeta-selective small molecule

Cancer Chemother Pharmacol. 2002 Jan;49(1):69-77. doi: 10.1007/s00280-001-0386-2.


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.

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Aorta, Thoracic / cytology
  • Aorta, Thoracic / drug effects
  • Basic Helix-Loop-Helix Transcription Factors
  • Carcinoma, Small Cell / blood supply
  • Carcinoma, Small Cell / pathology
  • Cornea / blood supply
  • Cornea / pathology
  • Endothelial Growth Factors / pharmacology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / pathology
  • Lymphokines / pharmacology
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / prevention & control
  • Organic Chemicals
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C beta
  • Rats
  • Rats, Inbred F344
  • Trans-Activators / pharmacology
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • 317615 x 2HCl
  • Angiogenesis Inducing Agents
  • Angiogenesis Inhibitors
  • Antineoplastic Agents, Alkylating
  • Basic Helix-Loop-Helix Transcription Factors
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Isoenzymes
  • Lymphokines
  • Organic Chemicals
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • endothelial PAS domain-containing protein 1
  • Protein Kinase C
  • Protein Kinase C beta