The Stress Response: Implications for the Clinical Development of Hsp90 Inhibitors
The Stress Response: Implications for the Clinical Development of Hsp90 Inhibitors
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DOI：
10.2174/1568009033481787
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发表时间：
2003-01-01
影响因子：
3
通讯作者：
Falsey, Ryan
中科院分区：
文献类型：
--
作者：
Whitesell, Luke;Bagatell, Rochelle;Falsey, Ryan
在其作为分子伴侣的作用中，热休克蛋白作为细胞内蛋白质稳态的中心整合剂。作为该功能的一部分，它们指导细胞生长、分化和存活的许多关键调节因子的折叠、组装、细胞内处置和蛋白水解周转。因此，热休克蛋白在许多类型的癌症中过度表达并不奇怪，诱导应激反应实际上可能是细胞耐受恶性转化的遗传混乱特征所必需的。通过应激反应调节热休克蛋白水平是复杂的，但最近的数据表明，分子伴侣Hsp90起着关键作用。具体而言，热休克蛋白90抑制剂改变与热休克因子1（HSF 1），控制应激反应诱导的主导转录因子相关的多分子伴侣复合物，并刺激HSF 1激活的热休克基因表达。由于几个原因，这种热休克反应的诱导现已成为Hsp90抑制剂进一步临床开发的重要考虑因素。首先，应激反应受损的肿瘤似乎对Hsp90抑制特别敏感。其次，Hsp90抑制剂诱导应激反应提供了一个敏感的药效学终点，用于监测个体患者的药物作用。第三，Hsp90抑制剂与传统的DNA靶向化疗药物和新的分子靶向药物都显示出重要的治疗相互作用。这些相互作用至少部分是由于这些药物对应激反应的调节。最后，由Hsp90抑制剂诱导的应激反应可能在非肿瘤性疾病如心脏病、中风和神经退行性疾病中具有治疗益处。这些好处才刚刚开始探索。
In their role as molecular chaperones, heat shock proteins serve as central integrators of protein homeostasis within cells. As part of this function, they guide the folding, assembly, intracellular disposition and proteolytic turnover of many key regulators of cell growth, differentiation and survival. Not surprisingly then, heat shock proteins are over expressed in many types of cancer, and induction of the stress response may actually be required for cells to tolerate the genetic disarray characteristic of malignant transformation. Regulation of heat shock protein levels via the stress response is complex, but recent data indicate that the molecular chaperone Hsp90 plays a key role. Specifically, Hsp90 inhibitors alter the multi-chaperone complexes associated with Heat Shock Factor 1 (HSF1), the dominant transcription factor controlling induction of the stress response, and stimulate HSF1-activated heat shock gene expression. Induction of this heat shock response has now emerged as an important consideration in the further clinical development of Hsp90 inhibitors for several reasons. First, tumors in which the stress response is compromised appear particularly sensitive to Hsp90 inhibition. Second, induction of the stress response by Hsp90 inhibitors provides a sensitive pharmacodynamic endpoint with which to monitor drug action in individual patients. Third, Hsp90 inhibitors display important therapeutic interactions with both conventional DNA-targeted chemotherapeutics and newer molecularly targeted agents. These interactions are, at least in part, due to modulation of the stress response by these drugs. Lastly, stress response induction by Hsp90 inhibitors may have therapeutic benefits in non-neoplastic disorders such as heart disease, stroke and neurodegenerative diseases. These benefits are just beginning to be explored.