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.
Teicher
Beverly A
BA
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. TEICHER_BEVERLY_A@Lilly.com
Alvarez
Enrique
E
Menon
Krishna
K
Esterman
Michail A
MA
Considine
Eileen
E
Shih
Chuan
C
Faul
Margaret M
MM
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins; D018288:Carcinoma, Small Cell / Q000098:blood supply / Q000473:pathology; D003315:Cornea / Q000098:blood supply / Q000473:pathology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009930:Organic Chemicals; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051381:Rats; D011916:Rats, Inbred F344; D015534:Trans-Activators / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D051792:Basic Helix-Loop-Helix Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008222:Lymphokines; D009930:Organic Chemicals; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C436248:317615 x 2HCl