Extracellular Hsp90 (eHsp90) as the actual target in clinical trials: intentionally or unintentionally.
Extracellular Hsp90 (eHsp90) as the actual target in clinical trials: intentionally or unintentionally.
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DOI：
10.1016/b978-0-12-407697-6.00005-2
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发表时间：
2013
影响因子：
--
通讯作者：
Woodley, David T.
中科院分区：
文献类型：
--
作者：
Li, Wei;Tsen, Fred;Sahu, Divya;Bhatia, Ayesha;Chen, Mei;Multhoff, Gabriele;Woodley, David T.
尽管在过去的二十年中进行了广泛的调查研究和临床试验，但我们仍然不明白为什么癌细胞对Hsp 90抑制剂的细胞毒性比正常细胞更敏感。我们仍然不明白为什么只有一些癌细胞对Hsp 90抑制剂敏感。基于过去几年的研究，我们认为癌细胞对Hsp 90抑制剂如17-N-烯丙基氨基-17-去甲氧基格尔德霉素的选择性敏感性是由于这些抑制剂抑制细胞外Hsp 90（eHsp 90）而不是细胞内Hsp 90。因为并非所有的肿瘤细胞都利用eHsp 90进行运动、侵袭和转移，所以只有“eHsp 90依赖性”癌细胞对Hsp 90抑制剂敏感。如果这些观点被证明是正确的，那么选择性靶向eHsp 90的药物制剂应该比目前无差别地靶向细胞外和细胞内Hsp 90的抑制剂对肿瘤细胞更有效，对正常细胞的毒性更小。
Despite extensive investigative studies and clinical trials over the past two decades, we still do not understand why cancer cells are more sensitive to the cellular toxicity of Hsp90 inhibitors than normal cells. We still do not understand why only some cancer cells are sensitive to the Hsp90 inhibitors. Based on studies of the past few years, we argue that the selected sensitivity of cancer cells to Hsp90 inhibitors, such as 17-N-allylamino-17-demethoxygeldanamycin, is due to inhibition of the extracellular Hsp90 (eHsp90) rather than intracellular Hsp90 by these inhibitors. Because not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only the group of “eHsp90-dependent” cancer cells is sensitive to Hsp90 inhibitors. If these notions prove to be true, pharmaceutical agents that selectively target eHsp90 should be more effective on tumor cells and less toxic on normal cells than current inhibitors that nondiscriminatively target both extracellular and intracellular Hsp90.