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首页> 外文期刊>Journal of Chemical Biology >Conditional drug screening shows that mitotic inhibitors induce AKT/PKB-insensitive apoptosis
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Conditional drug screening shows that mitotic inhibitors induce AKT/PKB-insensitive apoptosis

机译：条件药物筛选显示有丝分裂抑制剂诱导AKT / PKB不敏感凋亡

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摘要

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently upregulated in human cancer. Activation of this pathway has been reported to be associated with resistance to various chemotherapeutical agents. We here used a chemical biology/chemical informatic approach to identify apoptotic mechanisms that are insensitive to activation of the PI3K/AKT pathway. The National Cancer Institute (NCI) Mechanistic Set drug library was screened for agents that induce apoptosis in colon carcinoma cells expressing a constitutively active form of AKT1. The cytotoxicity screening data available as self-organized maps at the Developmental Therapeutics Program (DTP) of the NCI was then used to classify the identified compounds according to mechanism of action. The results showed that drugs that interfere with the mitotic process induce apoptosis which is comparatively insensitive to constitutive AKT1 activity. The conditional screening approach described here is expected to be useful for identifying relationships between the state of activation of signaling pathways and sensitivity to anticancer agents.
机译：磷脂酰肌醇3-激酶（PI3K）/ AKT途径在人类癌症中经常被上调。据报道该途径的激活与对各种化学治疗剂的抗性有关。我们在这里使用化学生物学/化学信息学方法来鉴定对PI3K / AKT途径的激活不敏感的凋亡机制。筛选了美国国家癌症研究所（NCI）机制集药物库中诱导表达AKT1组成型活性形式的结肠癌细胞凋亡的药物。 NCI的发展治疗学计划（DTP）提供的自组织图可作为细胞毒性筛选数据，然后根据作用机理对鉴定出的化合物进行分类。结果表明，干扰有丝分裂过程的药物会诱导凋亡，而凋亡对组成型AKT1活性相对不敏感。预期本文所述的条件筛选方法可用于鉴定信号通路激活状态与对抗癌药敏感性之间的关系。

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  • 来源
    《Journal of Chemical Biology》 |2009年第2期|81-87|共7页
  • 作者

    Maria Berndtsson; Emma Hernlund; Maria C. Shoshan; Stig Linder;

  • 作者单位

    Cancer Center Karolinska Department of Oncology and Pathology Karolinska Institute and Hospital Cancer Center Karolinska R8:00 S-171 76 Stockholm Sweden;

    Cancer Center Karolinska Department of Oncology and Pathology Karolinska Institute and Hospital Cancer Center Karolinska R8:00 S-171 76 Stockholm Sweden;

    Cancer Center Karolinska Department of Oncology and Pathology Karolinska Institute and Hospital Cancer Center Karolinska R8:00 S-171 76 Stockholm Sweden;

    Cancer Center Karolinska Department of Oncology and Pathology Karolinska Institute and Hospital Cancer Center Karolinska R8:00 S-171 76 Stockholm Sweden;

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  • 正文语种 eng
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  • 关键词

    Chemical biology; Apoptosis; AKT; Microtubuli-interacting agents;

    机译：化学生物学;细胞凋亡;AKT;微管相互作用剂;

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