Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
Int J Oncol. 2012 Jul;41(1):46-52. doi: 10.3892/ijo.2012.1419. Epub 2012 Mar 28.
Our previous study showed that the combination of a histone deacetylase (HDAC) inhibitor and an HIV protease inhibitor is effective against renal cancer cells. Because HDAC inhibition disrupts the chaperon function of heat shock protein (HSP) 90, we hypothesized that the combination of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, and the HIV protease inhibitor ritonavir would also act against renal cancer. The combination of 17-AAG and ritonavir induced apoptosis and inhibited the proliferation of renal cancer cells effectively. It also suppressed the expression of cyclin-dependent kinase 4 and cyclin D1, leading to the accumulation of the cells in the sub-G1 fraction. The expression of HSPs 27, 70 and 90 was increased by 17-AAG alone but reduced by 17-AAG combined with ritonavir. The combination decreased the expression of heat shock factor-1 (HSF-1), an HSP transcription factor, and this might be one of the mechanisms of the effect of the combination. We have also found that silencing of HSF-1 by siRNA inhibited the proliferation of renal cancer cells and that in surgically resected specimens the levels of HSF-1 expression in renal cancer tissue are higher than those in normal parenchyma. This is the first study showing the beneficial effect of combining 17-AAG and ritonavir and our data suggest that HSF-1 may be a novel therapeutic target in the treatment of renal cancer.
我们之前的研究表明，组蛋白去乙酰化酶（HDAC）抑制剂与 HIV 蛋白酶抑制剂联合使用对肾癌细胞具有疗效。因为 HDAC 抑制会破坏热休克蛋白（HSP）90 的伴侣功能，所以我们假设 HSP90 的抑制剂 17-烯丙基-17-脱甲氧基格尔德霉素（17-AAG）与 HIV 蛋白酶抑制剂利托那韦的联合使用也会对肾癌细胞产生作用。17-AAG 和利托那韦的联合使用有效地诱导了肾癌细胞的凋亡并抑制了其增殖。它还抑制了细胞周期蛋白依赖性激酶 4 和细胞周期蛋白 D1 的表达，导致细胞在 sub-G1 期积累。单独使用 17-AAG 会增加 HSPs 27、70 和 90 的表达，但与利托那韦联合使用会降低其表达。该联合用药还降低了 HSP 转录因子热休克因子-1（HSF-1）的表达，这可能是该联合用药效果的机制之一。我们还发现，通过 siRNA 沉默 HSF-1 可以抑制肾癌细胞的增殖，并且在手术切除的标本中，肾癌细胞组织中 HSF-1 的表达水平高于正常组织。这是首次表明 17-AAG 和利托那韦联合使用具有有益效果的研究，并且我们的数据表明 HSF-1 可能是治疗肾细胞癌的一种新的治疗靶点。
