Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation.
Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation.
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DOI：
10.1016/j.ijrobp.2009.06.044
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发表时间：
2010-08-01
影响因子：
7
通讯作者：
Lu, Bo
中科院分区：
文献类型：
--
作者：
Willey, Christopher D.;Xiao, Dakai;Tu, Tianxiang;Kim, Kwang Woon;Moretti, Luigi;Niermann, Kenneth J.;Tawtawy, Mohammed N.;Quarles, Chad C.;Lu, Bo
由于血管生成在肿瘤生长/进展中的重要作用，特别是与放射治疗等细胞毒性治疗相结合时，血管生成已引起肿瘤学的兴趣。在影响血管生长和稳定性的众多途径中，抑制蛋白激酶B(Akt)或蛋白激酶C(PKC)可以影响肿瘤微血管内的肿瘤血管。因此，我们想要确定PKC抑制是否能使肺肿瘤对辐射敏感。在细胞培养和小鼠肺癌模型中应用了选择性蛋白激酶Cβ抑制剂恩施他汀(ENZ，LY317615)和电离辐射的联合作用。用免疫印迹法、细胞毒试验(包括细胞增殖和克隆形成试验)以及Matrigel内皮管形成试验对肺癌细胞系和人脐静脉内皮细胞(HUVEC)进行检测。在体内，用免疫组织化学(IHC)检测了H460肺癌移植瘤的血管生成和增殖情况。在体外模型中，ENZ能有效地增敏HUVEC。此外，肺癌移植瘤的同步Enz治疗增强了IHC对放射诱导的肿瘤血管的破坏和增殖。然而，与单独治疗相比，联合治疗并不能增强肿瘤的生长延迟。对下游效应的分析表明，HUVEC和肺癌细胞株对ENZ和辐射的反应不同，因此只有HUVEC表现出mTOR下游的磷酸化S6抑制。当ENZ与mTOR抑制剂雷帕霉素联合应用于H460肺癌细胞时，可观察到放射增敏作用。PKC似乎是血管生成的关键，ENZ对其的抑制有可能加强体内的放射治疗。
Angiogenesis has generated interest in oncology due to its important role in cancer growth/progression, particularly when combined with cytotoxic therapies, such as radiotherapy. Among the numerous pathways influencing vascular growth and stability, inhibition of protein kinase B(Akt) or protein kinase C(PKC) can influence tumor blood vessels within tumor microvasculature. Therefore, we wanted to determine whether PKC inhibition could sensitize lung tumors to radiation. The combination of the selective PKCβ inhibitor Enzastaurin(ENZ, LY317615) and ionizing radiation were used in cell culture and a mouse model of lung cancer. Lung cancer cell lines and human umbilical vascular endothelial cells(HUVEC) were examined using immunoblotting, cytotoxic assays including cell proliferation and clonogenic assays as well as Matrigel endothelial tubule formation. In vivo, H460 lung cancer xenografts were examined for tumor vasculature and proliferation using immunohistochemistry(IHC). ENZ effectively radiosensitizes HUVEC within in vitro models. Furthermore, concurrent ENZ treatment of lung cancer xenografts enhanced radiation-induced destruction of tumor vasculature and proliferation by IHC. However, tumor growth delay was not enhanced with combination treatment compared to either treatment alone. Analysis of downstream effectors revealed that HUVEC and the lung cancer cell lines differed in their response to ENZ and radiation such that only HUVEC demonstrate phosphorylated S6 suppression, which is downstream of mTOR. When ENZ was combined with the mTOR inhibitor, rapamycin, in H460 lung cancer cells, radiosensitization was observed. PKC appears to be crucial for angiogenesis and its inhibition by ENZ has potential to enhance radiotherapy in vivo.
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影响因子：
11.2
作者：
Lee, Keun-Wook;Kim, Sang Gyun;Bang, Yung-Jue
通讯作者：
Bang, Yung-Jue
影响因子：
11.2
作者：
Tabatabai, Ghazaleh;Frank, Brigitte;Wick, Wolfgang
通讯作者：
Wick, Wolfgang
影响因子：
11.2
作者：
Graff, JR;McNulty, AM;Thornton, D
通讯作者：
Thornton, D
影响因子：
8.4
作者：
Jasinski, Piotr;Terai, Kaoru;Dudek, Arkadiusz Z.
通讯作者：
Dudek, Arkadiusz Z.
影响因子：
11.2
作者：
Tan, JH;Geng, L;Hallahan, DE
通讯作者：
Hallahan, DE