| Enzastaurin is a selective PKCβ (protein kinase C β) inhibitor. The IC50 of enzastaurin is 6, 39, 83 and 110 nM against PKCβ, PKCα, PKCγ and PKCε, respectively. Enzastaurin suppresses the proliferation of U87MG glioblastoma cells, PC-3 prostate carcinoma cells, and HCT116 colon carcinoma cells. Enzastaurin induces apoptosis of HCT116 colon carcinoma cells in a dose-dependent manner with the percentage of TUNEL positive cells increasing from a basal level of roughly 2% to >50% in HCT116 cells treated with 4 µM enzastaurin. Enzastaurin induces apoptosis in cultured human cancer cell lines in the low micromolar range (1-4 µM). Enzastaurin suppresses the proliferation of a wide array of cancer cell lines including K-562, MOLT-4, HOP-92, and PC-3. Enzastaurin suppresses GSK3βSer9 phosphorylation in both xenograft tissues and peripheral blood mononuclear cells. [1] Enzastaurin blocks phosphorylation of GSK3β and ribosomal protein S6. Enzastaurin specifically inhibits phorbol ester??nduced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCµ. Importantly, enzastaurin also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells.[2] Enzastaurin downregulates the expression of several PKC isoforms including PKCβII PKCθ, PKCε and/or their phosphorylation in GNAQ mutant cells. Enzastaurin exhibits greater antiproliferative effect on GNAQ mutant cells than wild type cells through induction of G1 arrest and apoptosis. Enzastaurin reduces the expression of antiapoptotic Bcl-2 and survivin in GNAQ mutant cells.[3] Enzastaurin induces a significant decrease of proliferation at 48 hours in WM (waldenström macroglobulinemia) cell lines with IC50 ranging from 2.5 to10 µM. In addition, enzastaurin overcome tumor cell growth induced by coculture of WM cells with bone marrow stromal cells. Enzastaurin induces dose-dependent apoptosis at 48 hours mediated via induction of caspase-3, caspase-8, caspase-9, and PARP cleavage. Enzastaurin inhibits Akt phosphorylation and Akt kinase activity, as well as downstream p-MARCKS and ribosomal p-S6.[4] Enzastaurin decreases microvessel density and VEGF expression in human tumor xenografts. In the HCT116 xenograft-bearing mice, plasma exposure for enzastaurin is ∼2 µM at 30 minutes, increases to nearly 3 µM at 1 hour, and drops to 1.5 µM by 2 hours.[1] Tumor growth, survival, and angiogenesis are abrogated by enzastaurin in an in vivo xenograft model of human MM (multiple myeloma).[2] Enzastaurin significantly inhibits tumor growth in an in vivo xenograft model of human WM in mice.[4] |
