Protein kinase C-beta as a therapeutic target in breast cancer.
Combining existing breast cancer therapies with novel agents that interfere with major signaling pathways is a promising approach. Targeting protein kinase C (PKC)-beta may serve as an attractive candidate in this regard for the following reasons: first, PKC-beta II (a splice variant of PKC-beta) has been implicated in tumorigenesis in human and rodent models. Second, PKC-beta, mainly PKC-betaII, is the predominant mediator of vascular endothelial growth factor-induced endothelial cell proliferation, which is a well-known stimulator of tumor angiogenesis and growth in breast cancer. There is increasing evidence that PKC-beta-selective inhibitors are effective in both preclinical and clinical trials. Enzastaurin, a potent inhibitor of PKC-beta, suppresses both tumor growth and tumor-induced angiogenesis in human tumor xenografts. Phase II trials of enzastaurin in recurrent high-grade gliomas and lymphomas have shown promising results. A similar compound, ruboxistaurin, is also under investigation in clinical trials for diabetic complications. This review focuses on the rationale for using PKC-beta as a therapeutic target at both the preclinical and clinical levels in breast cancer.
Sledge
George W
GW
Departments of Medicine and Pathology, Indiana University Cancer Center, Indianapolis, IN 46220, USA. gsledge@iupui.edu
Gökmen-Polar
Yesim
Y
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000209:etiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D064546:Protein Kinase C beta; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D004791:Enzyme Inhibitors; D007211:Indoles; D042461:Vascular Endothelial Growth Factor A; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin