Cisplatin abrogates the geldanamycin-induced heat shock response.
Cisplatin abrogates the geldanamycin-induced heat shock response.
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DOI：
10.1158/1535-7163.mct-08-0157
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发表时间：
2008-10
影响因子：
5.7
通讯作者：
Erlichman C
中科院分区：
文献类型：
--
作者：
McCollum AK;Lukasiewicz KB;Teneyck CJ;Lingle WL;Toft DO;Erlichman C
苯醌安莎霉素类抗生素如格尔德霉素（GA）与Hsp 90的N-末端ATP结合结构域结合并抑制其分子伴侣功能。尽管体外和体内研究表明有希望的抗肿瘤活性，但GA的衍生物，包括17-AAG，作为单一药物几乎没有临床疗效。因此，17-AAG和几种癌症化疗药物，包括顺铂（CDDP）的联合研究已经开始。在集落形成测定中，CDDP和GA或17-AAG的组合是协同的，并且与单独的每种药剂相比引起细胞凋亡增加。用Hsp 90靶向剂治疗产生的一种可测量的反应是诱导HSF-1热休克反应。用GA + CDDP处理揭示了CDDP抑制HSF-1转录的上调，导致应激诱导蛋白如Hsp 27和Hsp 70的水平降低。然而，CDDP治疗并没有阻止三聚体和核定位的HSF-1，但抑制DNA结合的HSF-1的染色质免疫沉淀证明。美法仑，而不是喜树碱，引起类似的抑制GA诱导的HSF-1介导的Hsp 70上调。MTS细胞存活测定显示，Hsp 70的缺失导致对GA的敏感性增加（Hsp 70 +/+ IC 50 =63.7±14.9 nM和Hsp 70 −/− IC 50 =4.3±2.9 nM），这证实了应激反应在降低GA敏感性中起关键作用。我们的研究结果表明，GA + CDDP的协同作用，部分是由于CDDP介导的废除热休克反应通过抑制HSF-1活性。HSF-1介导的热休克反应的临床调节可增强Hsp 90导向治疗的功效。
Benzoquinone ansamycin antibiotics such as geldanamycin (GA) bind to the N-terminal ATP binding domain of Hsp90 and inhibit its chaperone functions. Despite in vitro and in vivo studies indicating promising antitumor activity, derivatives of GA, including 17-AAG have demonstrated little clinical efficacy as single agents. Thus, combination studies of 17-AAG and several cancer chemotherapeutics, including cisplatin (CDDP), have begun. In colony-forming assays, the combination of CDDP and GA or 17-AAG was synergistic, and caused increased apoptosis compared to each agent alone. One measurable response that results from treatment with Hsp90-targeted agents is the induction of an HSF-1 heat shock response. Treatment with GA + CDDP revealed that CDDP suppresses upregulation of HSF-1 transcription, causing decreased levels of stress-inducible proteins such as Hsp27 and Hsp70. However, CDDP treatment did not prevent trimerization and nuclear localization of HSF-1, but inhibited DNA binding of HSF-1 as demonstrated by chromatin immunoprecipitation. Melphalan, but not camptothecin, caused similar inhibition of GA-induced HSF-1-mediated Hsp70 upregulation. MTS cell survival assays revealed that deletion of Hsp70 caused increased sensitivity to GA (Hsp70+/+ IC50=63.7±14.9 nM and Hsp70−/− IC50=4.3±2.9 nM), which confirmed that a stress response plays a critical role in decreasing GA sensitivity. Our results suggest that the synergy of GA + CDDP is due, in part, to CDDP-mediated abrogation of the heat shock response through inhibition of HSF-1 activity. Clinical modulation of the HSF-1-mediated heat shock response may enhance the efficacy of Hsp90-directed therapy.