Cotreatment小说磷酸肌醇类似物抑制剂和卡莫司汀增强化疗疗效,衰减在神经胶质瘤AKT活动。

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范米TE, Broaddus WC,现金D,菲尔莫H

Cotreatment小说磷酸肌醇类似物抑制剂和卡莫司汀增强化疗疗效,衰减在神经胶质瘤AKT活动。

癌症。2006年11月15日,107 (10):2446 - 54。

PubMed ID

17041888 (在PubMed

]

文摘

活动背景:加强一种蛋白激酶信号通路是著名的恶性神经胶质瘤,建议在治疗中发挥作用。因此,选择性的针对一种蛋白激酶,可能会增加化学敏感性。最近,一类小说AKT-selective抑制剂已被描述,包括SH-6、磷脂酰肌醇类似物。方法:SH-6的影响在神经胶质瘤细胞一种蛋白激酶信号进行测试,和公认的一种蛋白激酶信号在药物抗性中的作用被衰减测试一种蛋白激酶信号药物和基因。SH-6包括治疗神经胶质瘤细胞的初始特征随着剂量的SH-6 (0.30 -30 microM)和检查效果的一种蛋白激酶信号蛋白激酶的免疫印迹分析和化验与免疫沉淀反应AKT1。剂量反应研究SH-6管理使用发光细胞活力神经胶质瘤细胞株进行试验(0.1 -30 microM)。研究卡莫司汀的影响,无论是单独或结合磷脂酰肌醇3-kinase抑制剂LY294002或SH-6,是由细胞生存能力分析和单独生存分析。卡莫司汀的影响AKT活动作为对治疗的反应也被检查。半胱天冬酶分析被用来研究细胞凋亡在SH-6 /卡莫司汀的潜在作用引起细胞死亡。最后,感应的显性负AKT1转基因与卡氮芥结合使用来演示在卡莫司汀AKT1化疗的作用。 RESULTS: Serum-stimulated phosphorylation of AKT1 was inhibited by SH-6 at doses > or =10 microM (>70% decrease in Threonine 308 and Serine 473 phosphorylation of AKT1). In adenosine triphosphate assays, 72 hours of treatment with SH-6 led to 50% lethal doses near 10 microM for 2 cell lines tested. SH-6 enhancement of carmustine-mediated cell death led to synergistic increases in Caspase 3/Capsase 7 activity, implicating apoptosis as the cell death mechanism. In clonogenic assays, SH-6 cotreatment with carmustine significantly decreased the number of colonies at 10 microM (P < .05) compared with carmustine alone. No decrease was observed in cells that were treated with SH-6 alone (10 microM). LY294002 (10 microM) was also able to enhance the effects of carmustine significantly in both cell lines. CONCLUSIONS: In the current study, the authors characterized the efficacy of a new class of adjuvant chemotherapeutics that show promise in enhancing the efficacy of standard chemotherapy regimens in gliomas.

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药物靶点

药物	目标	类	生物	药理作用	行动
三磷酸腺苷	RAC-alpha丝氨酸/ threonine-protein激酶	蛋白质	人类	未知的	不可用	细节