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

O. Giles Best, S. P. Mulligan

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2314-2320
Number of pages7
JournalLeukemia & lymphoma
Volume53
Issue number11
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • Animals Apoptosis/drug effects CD40 Antigens/analysis CD40 Ligand/*analysis Cell Line, Tumor Cell Proliferation/drug effects Drug Resistance, Neoplasm HSP90 Heat-Shock Proteins/*antagonists & inhibitors Humans Immunophenotyping Isoxazoles/*administration & dosage Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/immunology Mice Phenotype Receptor Tyrosine Kinase-like Orphan Receptors/analysis Resorcinols/*administration & dosage STAT3 Transcription Factor/antagonists & inhibitors Stromal Cells/physiology Vidarabine/administration & dosage/*analogs & derivatives

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