17-Allylamino-17-demethoxygeldanamycin overcomes TRAIL resistance in colon cancer cell lines.
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.
University of Pennsylvania Cancer Center, 1020 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA. vasilevs@mail.med.upenn.edu
Irina A
IA
Vasilevskaya
Peter J
PJ
O'Dwyer
D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D004357:Drug Synergism; D006801:Humans; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins / Q000502:physiology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins; D009944:Organoplatinum Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000077150:Oxaliplatin; D017828:Rifabutin; C112765:tanespimycin