Antiangiogenic effects of a protein kinase Cβ-selective small molecule

Teicher, Beverly A.; Alvarez, Enríque; Menon, Krishna; Esterman, Michail A.; Considine, Eileen L.; Shih, Chuan; Faul, Margaret M.

doi:10.1007/s00280-001-0386-2

Cited by 91 publications

(61 citation statements)

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“…Enzastaurin is a potent inhibitor of PKCh (71). Endogenous PKChII mRNA levels in HCT116 cells were significantly reduced by enzastaurin, consistent with the effect on PKCh promoter activity (72).…”

Section: Pkc Inhibitorsmentioning

confidence: 57%

“…Enzastaurin at 10 mg/kg orally twice per day for 10 days postsurgical implant of VEGF-impregnated filters resulted in markedly decreased vascular growth to about one-half of the VEGF-stimulated controls, whereas 30 mg/kg decreased vascular growth to the level of surgical control (71). Enzastaurin at 30 mg/kg orally twice per day for 10 days post-surgical implantation of basic fibroblast growth factor resulted in decreased vascular growth to 26% of the basic fibroblast growth factor control.…”

Section: Pkc Inhibitorsmentioning

confidence: 99%

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Protein Kinase C as a Therapeutic Target

Teicher¹

2006

Clinical Cancer Research

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Section: Pkc Inhibitorsmentioning

confidence: 57%

Section: Pkc Inhibitorsmentioning

confidence: 99%

Protein Kinase C as a Therapeutic Target

Teicher¹

2006

Clinical Cancer Research

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“…Enzastaurin was developed as an ATP-competitive, selective inhibitor of PKCh with an IC 50 for PKCh of 6 nmol/L ( Table 1). As such, enzastaurin was developed as an antiangiogenic therapy for cancer (17)(18)(19). PKC activation has now been implicated in tumor cell proliferation and apoptosis as well (1).…”

Section: Resultsmentioning

confidence: 99%

“…Based upon the role established for PKCh in angiogenic signaling (1,3), enzastaurin was initially evaluated in preclinical tumor models for antiangiogenic activity. Enzastaurin treatment dramatically suppressed the growth of new vasculature towards a VEGF-impregnated disc implanted in the rat corneal micropocket (18). Enzastaurin also decreased microvessel density and VEGF expression in human tumor xenografts (19).…”

Section: Introductionmentioning

confidence: 97%

The Protein Kinase Cβ–Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma Xenografts

et al. 2005

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Activation of protein kinase CB (PKCB) has been repeatedly implicated in tumor-induced angiogenesis. The PKCB-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKCB has now also been implicated in tumor cell proliferation, apoptosis, and tumor invasiveness. Herein, we show that Enzastaurin has a direct effect on human tumor cells, inducing apoptosis and suppressing the proliferation of cultured tumor cells. Enzastaurin treatment also suppresses the phosphorylation of GSK3B ser9 , ribosomal protein S6 S240/244 , and AKT Thr308 . Oral dosing with Enzastaurin to yield plasma concentrations similar to those achieved in clinical trials significantly suppresses the growth of human glioblastoma and colon carcinoma xenografts. As in cultured tumor cells, Enzastaurin treatment suppresses the phosphorylation of GSK3B in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3B phosphorylation to a similar extent in peripheral blood mononuclear cells (PBMCs) from these treated mice. These data show that Enzastaurin has a direct antitumor effect and that Enzastaurin treatment suppresses GSK3B phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3B phosphorylation may serve as a reliable pharmacodynamic marker for Enzastaurin activity. With previously published reports, these data support the notion that Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis.

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“…However, multiple mechanisms of action and cellular targets have been described that may account for the anti-melanoma activity of Enzastaurin. For example, Enzastaurin is able to inhibit tumor angiogenesis by interfering with VEGF function and production (Keyes et al, 2004;Teicher et al, 2002). Thus, Enzastaurin may inhibit tumor growth in part by targeting endothelial cells, which express PKCb (Xia et al, 1996).…”

Section: Protein Kinase C Inhibitors As Therapeutics For Melanomamentioning

confidence: 99%

Specifying protein kinase C functions in melanoma

Denning

2012

Pigment Cell Melanoma Res

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SummaryThe protein kinase C (PKC) family of serine/threonine protein kinases is a heterogeneous group of enzymes receiving and integrating signals involved in both normal melanocyte biology and melanoma pathology. Alterations in PKC enzyme expression and activation contribute to the malignant phenotype of melanoma in both oncogenic and tumor suppressive roles. Delineating the diverse and often context‐dependent functions of PKC enzymes in melanocyte/melanoma biology is key to capitalize on these kinases as drug targets. This review summarizes several of the diverse functions of PKC in melanocyte and melanoma biology with a focus on PKC enzyme regulation and function.

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Antiangiogenic effects of a protein kinase Cβ-selective small molecule

Abstract: 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.

Cited by 91 publications

References 0 publications

Protein Kinase C as a Therapeutic Target

Protein Kinase C as a Therapeutic Target

The Protein Kinase Cβ–Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma Xenografts

Specifying protein kinase C functions in melanoma

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