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


METHODS
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.
Böll
Boris
B
Laboratory of Immunotherapy, Department of Hematology and Oncology, University Hospital Cologne, Cologne, Germany. boris.boell@uk.koeln.de
Eltaib
Farag
F
Reiners
Katrin S
KS
von Tresckow
Bastian
B
Tawadros
Samir
S
Simhadri
Venkateswara R
VR
Burrows
Francis J
FJ
Lundgren
Karen
K
Hansen
Hinrich P
HP
Engert
Andreas
A
von Strandmann
Elke Pogge
EP
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006689:Hodgkin Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine; D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D011725:Pyridines; D000225:Adenine