Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C
Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C
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DOI：
10.1016/j.ejca.2008.03.024
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发表时间：
2008-06-01
影响因子：
8.4
通讯作者：
Dudek, Arkadiusz Z.
中科院分区：
文献类型：
--
作者：
Jasinski, Piotr;Terai, Kaoru;Dudek, Arkadiusz Z.
Enzavin（LY317615.HCI）是一种蛋白激酶C（PKC）-β抑制剂，对4 T1小鼠乳腺癌和人神经胶质瘤细胞具有放射增敏作用;然而，尚未评价该作用的确切机制。本研究探讨了enzaelatin和γ射线照射对MCF-7人乳腺癌细胞PKC活性的影响。Enzaelinin（5 μ M）与辐射（2-8戈伊）组合产生MCF-7克隆形成细胞存活的协同下降。用膜联蛋白V和7-氨基放线菌素D染色的MCF-7细胞的分析表明，与单独照射相比，enzaelein（3、5和7 μ M）和照射（10戈伊）引起的细胞凋亡呈剂量依赖性增加。这种促凋亡作用通过半胱天冬酶-3和-9活性的增加来证实。在MCF-7异种移植模型中，与未处理的对照相比，25戈伊照射使PKC-α活性增加2.5倍，而PKC-β活性增加2.5倍。β-II活性增加了1.8倍。辐射诱导的所有三种抗凋亡PKC亚型的激活被enzaelatin（75 mg/kg，每日两次，持续3天）预处理逆转。我们的结论是，enzavelin通过逆转PKC亚型的抗凋亡激活对MCF-7人异种移植肿瘤具有放射增敏作用。(C)2008爱思唯尔有限公司保留所有权利。
Enzastaurin (LY317615.HCI), a protein kinase C (PKC)-beta inhibitor, has a radiosensitising effect on 4T1 murine breast cancer and human glioma cells; however, the exact mechanism of this action has not been evaluated. The present study investigated the effects of enzastaurin and gamma irradiation on PKC activity in MCF-7 human breast cancer cells in vitro and in vivo. Enzastaurin (5 mu M) in combination with irradiation (2-8 Gy) produced a synergistic decline in MCF-7 clonogenic cell survival. Analysis of MCF-7 cells stained with Annexin V and 7-aminoactinomycin D showed a dose-dependent increase in apoptosis in response to enzastaurin (3, 5 and 7 mu M) and irradiation (10 Gy) compared to irradiation alone. This pro-apoptotic effect was confirmed by increases in caspase-3 and -9 activity. In a MCF-7 xenograft model, irradiation with 25 Gy increased PKC-alpha activity by 2.5-fold compared to untreated controls, whereas PKC-epsilon. and -beta II activity was increased by 1.8-fold. Radiation-induced activation of all three anti-apoptotic isoforms of PKC was reversed by pre-treatment with enzastaurin (75 mg/kg, twice daily for 3 days). We conclude that enzastaurin has a radiosensitising effect on MCF-7 human xenograft tumours through the reversal of anti-apoptotic activation of PKC isoforms. (C) 2008 Elsevier Ltd. All rights reserved.