Heat shock protein 90 as a molecular target for cancer therapeutics
Heat shock protein 90 as a molecular target for cancer therapeutics
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DOI：
10.1016/s1535-6108(03)00029-1
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发表时间：
2003-03-01
期刊：
影响因子：
50.3
通讯作者：
Neckers, L
中科院分区：
文献类型：
--
作者：
Isaacs, JS;Xu, WP;Neckers, L
癌症是一种以遗传不稳定为特征的疾病。尽管通过分子靶向识别新的治疗药物具有很强的特异性，并可降低全身毒性，但对单个蛋白质或信号通路的特异性抑制面临着被癌细胞固有的遗传可塑性颠覆的潜在危险。癌细胞非常善于适应有害环境。因此，激素依赖型肿瘤最终变得不依赖激素，要么通过受体突变，要么通过激活导致受体刺激的替代途径。同样，暴露在最初致命水平的化疗下的癌细胞最终会激活多个重叠的信号通路，以保护自己免受进一步伤害，而缺氧的肿瘤则会上调多方面的转录反应，使它们能够成功应对缺氧状态。如果有人假设癌细胞总是处于某种类型的中等到重度压力下，那么解决这种明显困境的方法可能是瞄准使癌细胞能够如此成功地适应压力的基本机制。细胞对压力的反应是通过增加合成大量分子伴侣(也称为热休克蛋白，或HSPs，因为它们最初是在暴露在高温下的细胞中观察到的)。顾名思义，这些看家蛋白帮助一般的蛋白质折叠，并防止非功能的副反应，如错误折叠或未折叠的蛋白质的非特异性聚集。然而，在过去的十年中，有一种伴侣蛋白，特别是热休克蛋白90(Hsp90)，已经成为癌细胞生存的首要因素。HSP90在肿瘤细胞中的表达水平是正常细胞的2-10倍，这表明它可能对肿瘤细胞的生长和/或生存至关重要。Hsp90的一种小分子抑制剂，苯醌氨基-17-烯丙氨基-17-去甲氧基格尔达那霉素(17-AAG)，已经在几种人的异种移植模型中显示出抗肿瘤活性，包括结肠癌、乳腺癌和前列腺癌(Basso等人，2002年；Kelland等人，1999年；Solit等人，2002年)。该药物目前正在完成多机构的第一阶段临床试验，第二阶段试验正在计划中。其他Hsp90抑制剂也处于不同的开发阶段。有关Hsp90抑制剂药物开发的详细综述，包括对药效学终点的讨论，请参阅Maloney和Workman最近的综述(2002)。为什么这个分子靶标最近引起了如此多的兴趣？
Cancer is a disease characterized by genetic instability. Although identification of novel therapeutic agents via molecular targeting offers the promise of great specificity coupled with reduced systemic toxicity, specific inhibition of individual proteins or signaling pathways faces the potential peril of being subverted by the inherent genetic plasticity of cancer cells. Cancer cells are very adept at adapting to noxious environments. Thus, hormone-dependent tumors eventually become hormone-independent, either by receptor mutation or via activation of alternative pathways leading to receptor stimulation. Similarly, cancer cells exposed to initially fatal levels of chemotherapy eventually activate multiple and overlapping signaling pathways to protect themselves from further harm, while tumors deprived of oxygen upregulate a multifaceted transcriptional response that allows them to cope successfully with the hypoxic state.If one assumes that cancer cells are always under moderate to severe stress of one type or another, an approach to this apparent dilemma might be to target the basic machinery that allows cancer cells to adapt so successfully to stress. Cells respond to stress by increasing synthesis of a number of molecular chaperones (also known as heat shock proteins, or Hsps, because they were first observed in cells exposed to elevated temperature). These housekeeping proteins, as their name implies, assist general protein folding and prevent nonfunctional side reactions such as the nonspecific aggregation of misfolded or unfolded proteins. However, within the last decade, one chaperone in particular, heat shock protein 90 (Hsp90), has emerged as being of prime importance to the survival of cancer cells. Hsp90 is constitutively expressed at 2-to 10-fold higher levels in tumor cells compared to their normal counterparts, suggesting that it may be critically important for tumor cell growth and/or survival. A small molecule inhibitor of Hsp90, the benzoquinone ansamycin 17-allylamino-17-desmethoxygeldanamycin (17-AAG), has shown antitumor activity in several human xenograft models, including colon, breast, and prostate cancer (Basso et al., 2002; Kelland et al., 1999; Solit et al., 2002). The drug is currently completing multi-institution phase I clinical trials, and phase II trials are being planned. Other Hsp90 inhibitors are also at various stages of development. For a detailed review of Hsp90 inhibitor drug development, including a discussion of pharmacodynamic endpoints, see the recent review by Maloney and Workman (2002). Why has this molecular target garnered so much recent interest?