Lee Keun-Wook, Kim Sang Gyun, Kim Hwang-Phill, Kwon Euna, You Jiran, Choi Hyung-Jun, Park Jung-Hyun, Kang Byeong-Cheol, Im Seock-Ah, Kim Tae-You, Kim Woo Ho, Bang Yung-Jue
Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Cancer Res. 2008 Mar 15;68(6):1916-26. doi: 10.1158/0008-5472.CAN-07-3195.
Activation of protein kinase C (PKC) has been implicated in gastric carcinogenesis. Enzastaurin is an oral ATP-competitive inhibitor of the PKC beta isozyme. Although enzastaurin was initially advanced to the clinic based on its antiangiogenic activity, it is also known to have a direct effect on a variety of human cancer cells, inducing apoptosis by inhibiting the Akt signal pathway. However, data on enzastaurin for gastric cancer are limited. Therefore, this study was performed to assess the antitumor activity of enzastaurin on gastric cancer cells and to investigate the underlying antitumor mechanisms. Enzastaurin suppressed the proliferation of cultured gastric cancer cells and the growth of gastric carcinoma xenografts. Enzastaurin did not have an effect on gastric cancer cell cycle progression; however, it had a direct apoptosis-inducing effect through the caspase-mediated mitochondrial pathway. Glycogen synthase kinase 3beta phosphorylation, a reliable pharmacodynamic marker of enzastaurin activity, and Akt phosphorylation were both decreased after treatment with enzastaurin. Although the p90 ribosomal S6 kinase (Rsk) was also dephosphorylated, Erk phosphorylation was not affected in the enzastaurin-treated gastric cancer cells. Enzastaurin activated Bad, one of the Bcl-2 proapoptotic proteins, through dephosphorylation at Ser(112), and depletion of Bad activity resulted in resistance to enzastaurin-induced apoptosis and cytotoxicity in gastric cancer cells. These data suggest that enzastaurin induces apoptosis through Rsk-mediated and Bad-mediated pathways, besides inhibiting the Akt signal cascade. Furthermore, enzastaurin had synergistic or additive effects when combined with 5-fluorouracil, cisplatin, paclitaxel, or irinotecan. These results warrant further clinical investigation of enzastaurin for gastric cancer treatment.
蛋白激酶C（PKC）的激活与胃癌发生有关。恩杂鲁胺是一种口服的PKCβ同工酶ATP竞争性抑制剂。尽管恩杂鲁胺最初是因其抗血管生成活性而进入临床试验，但它也已知对多种人类癌细胞有直接作用，通过抑制Akt信号通路诱导细胞凋亡。然而，关于恩杂鲁胺治疗胃癌的数据有限。因此，本研究旨在评估恩杂鲁胺对胃癌细胞的抗肿瘤活性，并探讨其潜在的抗肿瘤机制。恩杂鲁胺抑制培养的胃癌细胞增殖和胃癌异种移植瘤的生长。恩杂鲁胺对胃癌细胞周期进程没有影响；然而，它通过半胱天冬酶介导的线粒体途径具有直接的凋亡诱导作用。用恩杂鲁胺处理后，糖原合酶激酶3β磷酸化（恩杂鲁胺活性的可靠药效学标志物）和Akt磷酸化均降低。尽管p90核糖体S6激酶（Rsk）也发生了去磷酸化，但在恩杂鲁胺处理的胃癌细胞中，Erk磷酸化未受影响。恩杂鲁胺通过使Bcl-2促凋亡蛋白之一的Bad在Ser（112）位点去磷酸化而激活Bad，Bad活性的缺失导致胃癌细胞对恩杂鲁胺诱导的凋亡和细胞毒性产生抗性。这些数据表明，恩杂鲁胺除了抑制Akt信号级联反应外，还通过Rsk介导和Bad介导的途径诱导细胞凋亡。此外，恩杂鲁胺与5-氟尿嘧啶、顺铂、紫杉醇或伊立替康联合使用时具有协同或相加作用。这些结果值得对恩杂鲁胺用于胃癌治疗进行进一步的临床研究。
