Breinig Marco, Caldas-Lopes Eloisi, Goeppert Benjamin, Malz Mona, Rieker Ralf, Bergmann Frank, Schirmacher Peter, Mayer Matthias, Chiosis Gabriela, Kern Michael André
Department of General Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Hepatology. 2009 Jul;50(1):102-12. doi: 10.1002/hep.22912.
The inhibition of heat shock protein 90 (Hsp90) has emerged as a promising antineoplastic strategy in diverse human malignancies. Hsp90 has been predicted to be involved in hepatocellular carcinoma (HCC) development; however, its role in hepatocarcinogenesis remains elusive. Using chemically distinctive Hsp90 inhibitors, we show that Hsp90 capacitates the aberrant expression and activity of crucial hepatocarcinogenesis-driving factors (e.g., insulin-like growth factor receptor 1, hepatocyte growth factor receptor, protein kinase B, v-raf-1 murine leukemia viral oncogene homolog 1, and cyclin-dependent kinase 4). In vitro, Hsp90 inhibition with both geldanamycin analogs (17-allylamino-17-desmethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-desmethoxygeldanamycin (17-DMAG)) and the non-quinone compound 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (PU-H71) reduced the viability of various HCC cell lines, induced the simultaneous degradation of numerous hepatocarcinogenic factors, and caused substantial cell cycle arrest and apoptosis. In contrast, nontumorigenic hepatocytes were less susceptible to Hsp90 inhibition. Because conventional geldanamycin-derivate Hsp90 inhibitors induce dose-limiting liver toxicity, we tested whether novel Hsp90 inhibitors lacking the benzoquinone moiety, which has been deemed responsible for hepatotoxicity, can elicit antineoplastic activity without causing significant liver damage. In HCC xenograft mouse models, PU-H71 was retained in tumors at pharmacologically relevant concentrations while being rapidly cleared from nontumorous liver. PU-H71 showed potent and prolonged in vivo Hsp90 inhibitory activity and reduced tumor growth without causing toxicity.
Hsp90 constitutes a promising therapeutic target in HCC. Non-quinone Hsp90 inhibitors exhibit tumor-specific accumulation and exert potent antineoplastic activity without causing significant hepatotoxicity.
热休克蛋白90（Hsp90）的抑制已成为多种人类恶性肿瘤中一种有前景的抗肿瘤策略。Hsp90被预测参与肝细胞癌（HCC）的发展；然而，其在肝癌发生中的作用仍不清楚。使用化学性质不同的Hsp90抑制剂，我们发现Hsp90促进关键肝癌发生驱动因子（如胰岛素样生长因子受体1、肝细胞生长因子受体、蛋白激酶B、v-raf-1鼠白血病病毒癌基因同源物1和细胞周期蛋白依赖性激酶4）的异常表达和活性。在体外，格尔德霉素类似物（17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）和17-二甲基氨基乙氨基-17-去甲氧基格尔德霉素（17-DMAG））以及非醌类化合物8-（6-碘苯并[d][1,3]二氧杂环戊烯-5-基硫代）-9-（3-（异丙基氨基）丙基）-9H-嘌呤-6-胺（PU-H71）对Hsp90的抑制降低了各种HCC细胞系的活力，诱导多种致癌因子同时降解，并导致显著的细胞周期停滞和凋亡。相比之下，非致瘤性肝细胞对Hsp90抑制的敏感性较低。由于传统的格尔德霉素衍生的Hsp90抑制剂会诱导剂量限制性肝毒性，我们测试了缺乏被认为是肝毒性原因的苯醌部分的新型Hsp90抑制剂是否能在不引起显著肝损伤的情况下引发抗肿瘤活性。在HCC异种移植小鼠模型中，PU-H71以药理相关浓度保留在肿瘤中，同时从非肿瘤肝脏中迅速清除。PU-H71在体内显示出强大且持久的Hsp90抑制活性，并减少肿瘤生长而不引起毒性。
Hsp90是HCC中一个有前景的治疗靶点。非醌类Hsp90抑制剂表现出肿瘤特异性蓄积，并在不引起显著肝毒性的情况下发挥强大的抗肿瘤活性。
