Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin's lymphoma cells for natural killer cell-mediated cytotoxicity.

Abstract

PURPOSE:

In Hodgkin's lymphoma, constitutive activation of NF-kappaB promotes tumor cell survival and proliferation. The molecular chaperone heat shock protein 90 (HSP90) has immune regulatory activity and supports the activation of NF-kappaB in Hodgkin's lymphoma cells.

EXPERIMENTAL DESIGN:

We analyzed the effect of HSP90 inhibition on viability and NF-kappaB activity in Hodgkin's lymphoma cells and the consequences for their recognition and killing through natural killer (NK) cells.

RESULTS:

The novel orally administrable HSP90 inhibitor BIIB021 (CNF2024) inhibited Hodgkin's lymphoma cell viability at low nanomolar concentrations in synergy with doxorubicin and gemcitabine. Annexin V/7-aminoactinomycin D binding assay revealed that BIIB021 selectively induced cell death in Hodgkin's lymphoma cells but not in lymphocytes from healthy individuals. We observed that BIIB021 inhibited the constitutive activity of NF-kappaB and this was independent of IkappaB mutations. Furthermore, we analyzed the effect of HSP90 inhibition on NK cell-mediated cytotoxicity. BIIB021 induced the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell-mediated killing. In a xenograft model of Hodgkin's lymphoma, HSP90 inhibition significantly delayed tumor growth.

CONCLUSIONS:

HSP90 inhibition has direct antitumor activity in Hodgkin's lymphoma in vitro and in vivo. Moreover, HSP90 inhibition may sensitize Hodgkin's lymphoma cells for NK cell-mediated killing via up-regulation of ligands engaging activating NK cell receptors.

• Authors: Boris Böll, Farag Eltaib, Katrin S Reiners, Bastian von Tresckow, Samir Tawadros, Venkateswara R Simhadri, Francis J Burrows, Karen Lundgren, Hinrich P Hansen, Andreas Engert, Elke Pogge von Strandmann
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 16 Pg. 5108-16 (Aug 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19671844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine
• Adjuvants, Immunologic
• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• NF-kappa B
• Pyridines
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Adjuvants, Immunologic (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Survival (drug effects)
• Cells, Cultured
• Cytotoxicity, Immunologic (drug effects)
• Down-Regulation (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Hodgkin Disease (immunology, pathology)
• Humans
• Killer Cells, Natural (drug effects, immunology, metabolism)
• Mice
• Mice, SCID
• NF-kappa B (metabolism)
• Pyridines (pharmacology)
• Xenograft Model Antitumor Assays