Chaperoning oncogenes: Hsp90 as a target of geldanamycin.
Chaperoning oncogenes: Hsp90 as a target of geldanamycin.
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DOI：
10.1007/3-540-29717-0_11
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发表时间：
2006
影响因子：
--
通讯作者：
L. Neckers
中科院分区：
文献类型：
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作者：
L. Neckers
热休克蛋白90 （Hsp90）是一些条件激活和/或表达的信号蛋白以及多种突变、嵌合和/或过度表达的信号蛋白的稳定性和功能所必需的分子伴侣，促进癌细胞生长和/或存活。Hsp90抑制剂通过与单个分子靶点特异性相互作用，导致Hsp90客户蛋白失活、不稳定和最终降解，并且在临床前模型系统中显示出有希望的抗肿瘤活性。一种Hsp90抑制剂17-AAG已完成I期临床试验，该药物的几项II期试验正在进行中。Hsp90抑制剂的独特之处在于，尽管它们是针对特定的分子靶点，但它们同时抑制多种频繁相互作用以促进癌细胞存活的信号通路。此外，通过抑制癌细胞利用的多个重叠生存途径中的节点，hsp90抑制剂与标准化疗药物的组合可能会显著提高标准药物的体内疗效。热休克蛋白90抑制剂可能会绕过癌细胞特有的遗传可塑性，这种可塑性使癌细胞最终能够逃避大多数分子靶向药物的毒性作用。基于机制的Hsp90抑制剂的使用，无论是单独使用还是与其他药物联合使用，都应该对多种形式的癌症有效。
Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, and/or over-expressed signaling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial and several Phase II trials of this agent are in progress. Hsp90 inhibitors are unique in that, although they are directed toward a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Further, by inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, a combination of an Hsp90inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitorsmay circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective towardmultiple forms of cancer.