The protein kinase Cβ-selective inhibitor, enzastaurin (LY317615.HCI), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts
The protein kinase Cβ-selective inhibitor, enzastaurin (LY317615.HCI), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts
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DOI：
10.1158/0008-5472.can-05-0071
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Thornton, D
中科院分区：
文献类型：
--
作者：
Graff, JR;McNulty, AM;Thornton, D
蛋白激酶C β（PKC β）的激活已反复参与肿瘤诱导的血管生成。PKC β-选择性抑制剂Enzaelatin（LY317615.HCl）可抑制血管生成，并基于这种抗血管生成活性进行了临床开发。PKC β的激活现在也与肿瘤细胞增殖、凋亡和肿瘤侵袭有关。在此，我们表明，Enzaelatin对人类肿瘤细胞有直接的作用，诱导细胞凋亡和抑制培养的肿瘤细胞的增殖。Enzalutamide治疗还抑制GSK 3 β（ser 9）、核糖体蛋白S6（S240/244）和AKT（Thr 308）的磷酸化。经口给予Enzaelatin以产生与临床试验中达到的血浆浓度相似的血浆浓度，可显著抑制人胶质母细胞瘤和结肠癌异种移植物的生长。在培养的肿瘤细胞中，Enzaelatin治疗抑制了这些异种移植肿瘤组织中GSK 3 β的磷酸化。在来自这些经处理小鼠的外周血单核细胞（PBMC）中，Enzavin处理也以类似程度抑制GSK 3 β磷酸化。这些数据表明，Enzavin具有直接的抗肿瘤作用，Enzavin治疗可抑制肿瘤组织和PBMC中的GSK 3 β磷酸化，表明GSK 3 β磷酸化可作为Enzavin活性的可靠药效学标志物。与先前发表的报告，这些数据支持的概念，Enzavin抑制肿瘤生长通过多种机制：直接抑制肿瘤细胞增殖和诱导肿瘤细胞死亡耦合抑制肿瘤诱导的血管生成的间接作用。
Activation of protein kinase C beta (PKC beta) has been repeatedly implicated in tumor-induced angiogenesis. The PKC beta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKC beta 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 GSK3 beta(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 GSK3 beta in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3 beta 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 GSK3 beta phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3 beta 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.