|
Protein Kinase C: Possibly a drug target for inhibiting
neovascularization in wet Age-related Macular Degeneration by Philip Filner, Ph.D. Protein kinases are
enzymes which catalyze the transfer of phosphate from adenosine-5'-triphosphate (ATP) to certain amino acid residues in certain proteins. Generally, the phosphorylation of a protein
changes its functionality, from inactive to active in some cases, and from active to inactive in others. Thus, phosphorylation is a means of up-regulating or down-regulating processes
controlled by specific proteins. One subgroup of protein kinases is protein kinase C, which catalyze the phosphorylation of tyrosine residues in certain proteins. A protein which
stimulates angiogenesis, e.g. of solid tumors, called Vascular Endotheelial Growth Factor (VEGF), depends in part on activation of a protein which is a receptor for VEGF. The
activation is achieved by phosphorylation of the VEGF receptor, which is catalyzed by a protein kinase C. Drugs which inhibit protein kinase C can promote death of tumor cells which
depend on VEGF-mediated angiogenesis (Yoshiji et al., 1999). A protein kinase C system can also act by stabilizing VEGF mRNA (Shih et al, 1999). RPE cells produce VEGF, and RPE
from eyes with Age Related Macular Degeneration produce larger amounts of VEGF (Kliffen et al, 1997). If Bruch's membrane is compromised, VEGF released by RPE cells can reach blood
vessels in the choroid and stimulate choroidal neovascularization. Seo et al. (1999) have shown in mouse that PKC412, an inhibitor of protein kinase C, can inhibit retinal
neovascularization stimulated by oxygen deprivation. |
|
|
The findings summarized above suggest the existence of the mechanism diagrammed in Fig.
1: If VEGF produced by RPE can cross Bruch's membrane, it can stimulate neovascularization via a pathway dependent on activation of a VEGF receptor by phosphorylation of tyrosine
residues, catalyzed by protein kinase C . Drugs which inhibit protein kinase C may be able to block this neovascularization pathway. Drug companies have been developing inhibitors
of protein kinase C because a number of processes important in certain diseases, notably solid tumors, are facilitated by the action of protein kinase C. Thus inhibitors of protein
kinase C have potential as anti-cancer drugs. Dr. P A Campochiaro of the Johns Hopkins Wilmer Eye Institute is organizing a clinical trial of PKC412, an inhibitor of protein kinase
C, to see if it a safe and effective inhibitor of neovascularization caused by diabetic retinopathy. In the future, the same or similar drugs probably will be tested as treatments for
neovascularizations caused by age related macular degeneration. References Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT
Increased expression of angiogenic growth factors in age-related
maculopathy. Br J Ophthalmol (1997) 81:154-62 Seo MS, Kwak, N, Ozaki H, Yamada H, Okamoto N, Yamada E, Fabbro D, Hofmann F, Wood JM, Campochiaro, PA
Dramatic inhibition of
retinal and choroidal neovascularizatrion by oral administration of a kinase inhibitor.
Amer J Pathology (1999) 154:1743-1753
Shih SC, Mullen A, Abrams K, Mukhopadhyay D, Claffey KP
Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human
glioblastoma cells. J Biol Chem (1999) 274(22):15407-14 Yoshiji H, Kuriyama S, Ways DK, Yoshii J, Miyamoto Y, Kawata M, Ikenaka Y, Tsujinoue H, Nakatani T, Shibuya M, Fukui H
Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis. Cancer Res (1999) 59:4413-4418 October 31, 1999
|
|
