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: Jeremy S Abramson, Wen Chen, Przemyslaw Juszczynski, Hidenobu Takahashi, Donna Neuberg, Jeffery L Kutok, Kunihiko Takeyama, Margaret A Shipp
• Journal: British journal of haematology (Br J Haematol) Vol. 144 Issue 3 Pg. 358-66 (Feb 2009) ISSN: 1365-2141 [Electronic] England
• PMID: 19036086 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Phosphoinositide-3 Kinase Inhibitors
• Protein Isoforms
• Protein Kinase Inhibitors
• RNA, Small Interfering
• tanespimycin
• Doxorubicin
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Benzoquinones (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Doxorubicin (pharmacology)
• Enzyme Activation
• Gene Deletion
• Gene Expression Profiling
• HSP90 Heat-Shock Proteins (analysis, antagonists & inhibitors, metabolism)
• Humans
• Lactams, Macrocyclic (pharmacology, therapeutic use)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, pathology)
• Oligonucleotide Array Sequence Analysis
• Phosphoinositide-3 Kinase Inhibitors
• Protein Isoforms (analysis, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Small Interfering (pharmacology)