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详细内容
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Enzastaurin is an ATP-competitive, selective oral inhibitor of protein kinase Cβ with IC50 value of 6 nM [1].
Protein kinase C (PKC) is a family of serine-threonine protein kinases that have been proved to play critical roles in the formation and progression of tumor cells. The PKCβ is especially found to contribute to the growth and proliferation of tumors such as diffuse large B-cell lymphoma, multiple myeloma and chronic lymphoid leukemia. The selective PKCβ inhibitor enzastaurin was found to have antiangiogenic activity in tumor model as well as suppress tumor proliferation and induce apoptosis. Besides that, enzastaurin showed the inhibitory effects on phosphorylation of ribosomal protein S6, GSK3β and AKT which are in pathways influenced by PKC. Due to these, enzastaurin was developed as a therapy for cancer [1 and 2].
Enzastaurin at low concentration suppressed cell proliferation of various tumor cells including colon carcinoma (HCT-116), glioblastoma (U87MG), non–small cell lung cancer (A549), melanoma (M14), ovarian cancer (OVCAR-3), breast cancer (MCF-7), leukemia (K562), prostate cancer (PC-3), renal cancer (CAKI-1) and central nervous system cancer (U251). Enzastaurin induced apoptosis of tumor cells at low concentration in a range of 1 to 4 μM and the apoptosis was proved to be caspase-independent. In addition, enzastaurin suppressed the phosphorylation ofGSK3βSer9, ribosomal protein S6Ser240/244 and AKTThr308 time-dependently in tumor cells and affected these pathways [1 and 3].
In mice models, oral administration of enzastaurin at a dose of 75 mg/kg resulted in significant proliferation inhibition of U87MG glioblastoma or HCT116 coloncarcinoma xenografts. In mice bearing human walden strommacro globulinemia xenografts, administration of enzastaurin at dose of 80 mg/kg significantly reduced tumor growth of WM and increased survival [1 and 2].
Reference:
[1] Graff J R, McNulty A M, Hanna K R, et al. 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. Cancer Research, 2005, 65(16): 7462-7469.
[2] Moreau A S, Jia X, Ngo H T, et al. Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstr mmacroglobulinemia. Blood, 2007, 109(11): 4964-4972.
[3] Rizvi M A, Ghias K, Davies K M, et al. Enzastaurin (LY317615), a protein kinase Cβ inhibitor, inhibits the AKT pathway and induces apoptosis in multiple myeloma cell lines. Molecular cancer therapeutics, 2006, 5(7): 1783-1789.
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