17-Allylamino-17-demethoxygeldanamycin overcomes TRAIL resistance in colon cancer cell lines

Biochem Pharmacol. 2005 Aug 15;70(4):580-9. doi: 10.1016/j.bcp.2005.05.018.


Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising candidate for treatment of cancer, but displays variable cytotoxicity in cell lines. The mechanisms of sensitivity and resistance have not been fully elucidated; both AKT and NF-kappaB pathways may modulate cytotoxic responses. We have shown that the Hsp90 inhibitor 17-AAG enhances the cytotoxicity of oxaliplatin in colon cancer cell lines through inhibition of NF-kappaB. We analyzed the effects of TRAIL and 17-AAG in combination in a series of nine colon cancer cell lines and characterized activation of the pathways to apoptosis. IC(50) values for a 72 h exposure to TRAIL ranged from 30 to 4000 ng/ml. Cytotoxicity assays demonstrated additivity or synergism of the TRAIL/17-AAG combination in all cell lines, with combination indices at IC(50) ranging from 0.53 to 1. The sensitizing effect of 17-AAG was greater in the TRAIL-resistant cell lines. In TRAIL-resistant cell lines, the combination of 17-AAG and TRAIL resulted in activation of both extrinsic and intrinsic apoptotic pathways, though with quantitative differences between HT29 and RKO cells: differential effects of 17-AAG on AKT and NF-kappaB characterized these cell lines. In both cell lines, the combination also led to down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and enhanced activation of caspase-3. We conclude that either AKT or NF-kappaB may promote resistance to TRAIL in colon cancer cells, and that the ability of 17-AAG to target multiple putative determinants of TRAIL sensitivity warrants their further investigation in combination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis Regulatory Proteins
  • Benzoquinones
  • Cell Line, Tumor
  • Colonic Neoplasms / pathology*
  • Drug Synergism
  • Humans
  • Lactams, Macrocyclic
  • Membrane Glycoproteins / physiology*
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • Rifabutin / analogs & derivatives*
  • Rifabutin / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / physiology*


  • Apoptosis Regulatory Proteins
  • Benzoquinones
  • Lactams, Macrocyclic
  • Membrane Glycoproteins
  • Organoplatinum Compounds
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Oxaliplatin
  • Rifabutin
  • tanespimycin