17-Allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1

Int J Oncol. 2012 Jul;41(1):46-52. doi: 10.3892/ijo.2012.1419. Epub 2012 Mar 28.

Abstract

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.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzoquinones / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Synergism
  • G1 Phase Cell Cycle Checkpoints
  • Gene Expression / drug effects*
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Heat Shock Transcription Factors
  • Humans
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / metabolism*
  • Lactams, Macrocyclic / pharmacology*
  • RNA Interference
  • Ritonavir / pharmacology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Antineoplastic Agents
  • Benzoquinones
  • CCND1 protein, human
  • DNA-Binding Proteins
  • HSP90 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Lactams, Macrocyclic
  • Transcription Factors
  • Cyclin D1
  • tanespimycin
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Ritonavir