Aspirin reduces the outcome of anticancer therapy in Meth A-bearing mice through activation of AKT-glycogen synthase kinase signaling
Aspirin reduces the outcome of anticancer therapy in Meth A-bearing mice through activation of AKT-glycogen synthase kinase signaling
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DOI：
10.1158/1535-7163.mct-05-0473
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发表时间：
2006-05-01
影响因子：
5.7
通讯作者：
Ricchi, Paolo
中科院分区：
文献类型：
--
作者：
di Palma, Antonella;Matarese, Giuseppe;Ricchi, Paolo
在毫摩尔浓度下，阿司匹林显示出几种独立于其抑制环加氧酶能力的机制。偶尔，在体外显示的机制与体内临床相关性的影响明确相关。越来越多的文献关注阿司匹林在神经退行性疾病中的细胞保护作用，以及AKT通路在神经保护中的激活和对抗癌药物的耐药诱导。在这项工作中，我们测试了阿司匹林激活甲基胆碱诱导的纤维肉瘤细胞（甲基苯丙胺A）移植到BALB/c裸鼠的AKT存活通路的能力，以及阿司匹林在依托泊苷（VP-16）为基础的抗癌治疗中的临床效果。我们发现阿司匹林在体外和体内均能减少vp -16诱导的细胞凋亡，激活AKT。在携带甲基苯丙胺的小鼠中，阿司匹林也激活了糖原合成酶激酶-3，并降低了VP-16共处理动物的抗癌治疗活性和疗效。我们的数据表明，阿司匹林的抗凋亡作用是通过激活akt -糖原合成酶激酶途径在体内起作用的，从而降低了基于vp -16的治疗的结果。这些发现可能对人类恶性肿瘤的治疗具有临床意义。
Aspirin displays, at millimolar concentrations, several mechanisms independent from its ability to inhibit cyclo-oxygenases. Occasionally, the mechanisms displayed in vitro have been clearly related to an effect of clinical relevance in vivo. An expanding literature has been focusing on the cytoprotective effect of aspirin in neurodegenerative disorders and the activation of AKT pathway in neuroprotection and induction of resistance to anticancer drugs. In this work, we tested the ability of aspirin to activate the AKT survival pathway in methylcholanthrene-induced fibrosarcoma cells (Meth A) transplanted into BALB/c nude mice and the clinical effect of aspirin cotreatment during etoposide (VP-16)-based anticancer therapy. We found that cotreatment with aspirin reduced VP-16-induced apoptosis and activated AKT in vitro and in vivo. In Meth A-bearing mice, aspirin administration also activated glycogen synthase kinase-3 and reduced the activity and the efficacy of anticancer therapy in VP-16 cotreated animals. Our data suggest that the antiapoptotic effect of aspirin operates in vivo through the activation of AKT-glycogen synthase kinase pathway causing a decrease in the outcome of VP-16-based therapy. These findings could have clinical relevance in treatment of human malignancies.