Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activity
Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activity
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DOI：
10.1093/annonc/mdg291
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发表时间：
2003-07-01
影响因子：
50.5
通讯作者：
Hidalgo, M
中科院分区：
文献类型：
--
作者：
deGraffenried, LA;Friedrichs, WE;Hidalgo, M
背景：他莫昔芬耐药是大量乳腺癌患者治疗失败的根本原因。Akt是磷脂酰肌醇3-激酶（PI 3 K）信号通路的下游介质，其活化被认为是他莫昔芬耐药的机制之一。Akt活性升高的乳腺癌通常与侵袭性疾病以及对化疗和化疗诱导的细胞凋亡的抵抗相关。抑制PI 3 K恢复过度活跃的Akt细胞对他莫昔芬的凋亡反应。因此，表现出Akt抑制特性的药剂是用于治疗乳腺癌抗性乳腺癌的有吸引力的治疗剂。n-3脂肪酸已被证明是有力的和有效的广谱蛋白激酶inhibitors.Materials and Methods：在这项研究中，我们证明，n-3脂肪酸，二十碳五烯酸（EPA），抑制Akt的激酶活性。结论：EPA对Akt高表达的乳腺癌耐药细胞有一定的治疗作用，为临床应用提供了理论依据。
Background: Tamoxifen resistance is the underlying cause of treatment failure in a significant number of patients with breast cancer. Activation of Akt, a downstream mediator in the phosphatidylinositol 3-kinase (PI3K) signaling pathway has been implicated as one of the mechanisms involved in tamoxifen resistance. Breast cancers with heightened Akt activity are frequently associated with an aggressive disease and resistance to chemo- and hormone-therapy-induced apoptosis. Inhibition of PI3K restores apoptotic response to tamoxifen in hyperactive Akt cells. Therefore, agents that demonstrate Akt inhibitory properties are attractive therapeutic agents for the treatment of hormone-resistant breast cancer. n-3 fatty acids have proven to be potent and efficacious broad-spectrum protein kinase inhibitors.Materials and methods: In this study we demonstrate that the n-3 fatty acid, eicosapentaenoic acid (EPA), inhibits the kinase activity of Akt. Co-treatment with EPA renders breast cancer cells that overexpress a constitutively active Akt more responsive to the growth inhibitory effects of tamoxifen by approximately 35%.Conclusions: These findings suggest that EPA may be useful for the treatment of tamoxifen-resistant breast cancer cells with high levels of activated Akt and provide the rationale to test this hypothesis in the clinic.