Heat shock protein-90 inhibitor, NVP-AUY922, is effective in combination with fludarabine against chronic lymphocytic leukemia cells cultured on CD40L-stromal layer and inhibits their activated/proliferative phenotype.
Chronic lymphocytic leukemia (CLL) involves disease infiltration into active proliferation centers within the lymph nodes and marrow. Successful treatment of CLL must involve targeting the leukemic cells in these supportive microenvironments. Our recent data suggest that inhibition of heat shock protein-90 (Hsp90) may be an effective treatment for CLL. We sought to further these data to determine whether the Hsp90 inhibitor, AUY922 (Novartis), is effective against CLL cells in a supportive in vitro environment. AUY922 significantly attenuated changes in immunophenotype and signal transducer and activator of transcription 3 (STAT3) signaling induced by CD40L-fibroblast co-culture but had no effect on the viability of CLL cells in this model. However, AUY922 in combination with fludarabine was significantly more effective at inducing apoptosis in cells in co-culture than either drug alone, an effect that was irrespective of ATM/TP53 dysfunction. In conclusion, our data suggest that further studies and clinical trials of AUY922 in combination with fludarabine may be warranted.
Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia. gilesbest@yahoo.com
O Giles
OG
Best
Stephen P
SP
Mulligan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000032:analysis; D023201:CD40 Ligand / Q000032:analysis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D016130:Immunophenotyping; D007555:Isoxazoles / Q000008:administration & dosage*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D010641:Phenotype; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000032:analysis; D012118:Resorcinols / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D017154:Stromal Cells / Q000502:physiology; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D019013:CD40 Antigens; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D023201:CD40 Ligand; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D014740:Vidarabine; C024352:fludarabine