title: The heat shock protein 90 inhibitor IPI-504 induces apoptosis of AKT-dependent diffuse large B-cell lymphomas.
abstract: Heat shock protein 90 (HSP90) is a molecular chaperone that stabilizes critical client proteins in multiple cancers. Gene expression profiling was utilized to characterize HSP90 isoform expression in primary human diffuse large B-cell lymphomas (DLBCLs). HSP90 alpha and beta isoforms were differentially expressed in subsets of tumours defined by their transcriptional profiles. Thereafter, we assessed the activity of the HSP90 inhibitor, IPI-504, in an extensive panel of DLBCL cell lines. IPI-504, which interacts with the conserved ATP-binding site in both HSP90 isoforms, inhibited proliferation and induced apoptosis in the majority of DLBCL cell lines at low micromolar concentrations. IPI-504-sensitive cell lines expressed high levels of the HSP90 client protein, pAKT, and exhibited dose-dependent decreases in pAKT levels following IPI-504 treatment and significantly reduced proliferation following AKT RNAi. Furthermore, the combination of low-dose (<1 micromol/l) IPI-504 and the AKT/Pi3K pathway inhibitor, LY24009, was synergistic in IPI-504-sensitive DLBCL cell lines. Low-dose IPI-504 was also synergistic with the chemotherapeutic agent, doxorubicin. The HSP90 inhibitor IPI-504 warrants further investigation in DLBCL alone and in combination with identified client protein inhibitors and active chemotherapeutic agents.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Abramson
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takeyama
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C112765:tanespimycin; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt