Enzastaurin (LY317615) is an ATP-competitive and selective inhibitor of PKCβ with an IC50 value of 6nM [1]. Enzastaurin reduces phosphor-Cdc25C levels, resulting in G2/M-checkpoint abrogation, and inhibits Akt and GSK3β phosphorylation as well as the secretion of VEGF [2]. Enzastaurin has been widely used to inhibit the phosphorylation level of GSK3β and to restrain the growth of various cancer cells[3].
In vitro, Enzastaurin treatment for 72 hours significantly inhibited the viability of SNU-620 cells and SNU-1 cells, with IC50 values of 3.56µM and 3.78µM, respectively[4]. Treatment with 20µM Enzastaurin for 48 hours significantly induced apoptosis in BCWM.1 cells, accompanied by an increase in the cleavage of caspase-8 and PARP[5]. Treatment with 10µM Enzastaurin for 24 hours significantly inhibited the migration and invasion of A549 cells, and led to a significant downregulation of the HIF1α, VEGFC, and u-PAR genes[6].
In vivo, Enzastaurin treatment via oral administration at a dose of 80mg/kg twice daily for one week significantly enhanced the vascular damage induced by 2Gy radiation in the H460 xenograft mouse model and inhibited tumor growth[7]. Daily subcutaneous injection of a 25mg/kg dose of Enzastaurin for three consecutive days impaired the memory and learning ability of middle-aged rats[8].
References:
[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[J]. Cancer research, 2005, 65(16): 7462-7469.
[2] Giovannetti E, Honeywell R, Hanauske A R, et al. Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small cell lung cancer (NSCLC)[J]. Current Drug Targets, 2010, 11(1): 12-28.
[3] Nakajima E, Helfrich B, Chan D, et al. Enzastaurin a protein kinase Cbeta-selective inhibitor, inhibits the growth of SCLC and NSCLC cell lines[J]. Journal of Clinical Oncology, 2006, 24(18_suppl): 13138-13138.
[4] Lee K W, Kim S G, Kim H P, et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells[J]. Cancer research, 2008, 68(6): 1916-1926.
[5] Moreau A S, Jia X, Ngo H T, et al. Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström macroglobulinemia[J]. Blood, The Journal of the American Society of Hematology, 2007, 109(11): 4964-4972.
[6] Körner A, Mudduluru G, Manegold C, et al. Enzastaurin inhibits invasion and metastasis in lung cancer by diverse molecules[J]. British journal of cancer, 2010, 103(6): 802-811.
[7] Willey C D, Xiao D, Tu T, et al. Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation[J]. International Journal of Radiation Oncology* Biology* Physics, 2010, 77(5): 1518-1526.
[8] Willeman M N, Mennenga S E, Siniard A L, et al. The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats[J]. PloS one, 2018, 13(6): e0198256.
Enzastaurin (LY317615)是一种ATP竞争性、选择性的PKCβ抑制剂，IC50值为6nM[1]。Enzastaurin可降低磷酸化Cdc25C水平，导致G2/M检查点功能丧失，并抑制Akt和GSK3β的磷酸化以及VEGF的分泌[2]。Enzastaurin已被广泛用于抑制GSK3β的磷酸化水平，并抑制多种癌细胞的生长[3]。
在体外，Enzastaurin处理72小时显著抑制了SNU-620细胞和SNU-1细胞的活力，IC50值分别为3.56µM和3.78µM[4]。使用20µM的Enzastaurin处理BCWM.1细胞48小时，显著诱导了细胞凋亡，同时伴随着caspase-8和PARP裂解的增加[5]。使用10µM的Enzastaurin处理A549细胞24小时，显著抑制了细胞的迁移和侵袭，并导致HIF1α、VEGFC和u-PAR基因显著下调[6]。
在体内，在H460异种移植小鼠模型中，每日两次口服80mg/kg剂量的Enzastaurin，持续一周，显著增强了2Gy辐射诱导的血管损伤并抑制了肿瘤生长[7]。连续三天每日皮下注射25mg/kg剂量的Enzastaurin，会损害中年大鼠的记忆和学习能力[8]。