Heat Shock Protein 90 Inhibitor BIIB021 (CNF2024) Depletes NF-κB and Sensitizes Hodgkin's Lymphoma Cells for Natural Killer Cell–Mediated Cytotoxicity

Abstract

Purpose: In Hodgkin's lymphoma, constitutive activation of NF-κB promotes tumor cell survival and proliferation. The molecular chaperone heat shock protein 90 (HSP90) has immune regulatory activity and supports the activation of NF-κB in Hodgkin's lymphoma cells. Experimental Design: We analyzed the effect of HSP90 inhibition on viability and NF-κB 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-κB and this was independent of IκB 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. (Clin Cancer Res 2009;15(16):5108-16) The ubiquitously expressed molecular chaperone heat shock protein 90 (HSP90) promotes tumor cell survival and proliferation by maintaining conformation, stability, and activity of several key oncogenic client proteins (1). Formation of HSP90 cochaperone complexes is essential for the function of HSP90 and requires ATP hydrolysis by a NH 2 -terminal ATPase.

Hsp90 inhibitor BIIB021 enhances triptolide-induced apoptosis of human T-cell acute lymphoblastic leukemia cells in vitro mainly by disrupting p53-MDM2 balance

“…Our data showed that BIIB021 could inhibit Akt protein expression and phosphorylation. Additionally, BIIB021 had a modest effect on p65 expression, a transcription factor of the NF-κB family ( Figure 2B), consistent with a previous report that BIIB021 inhibits constitutive NF-κB activity in Hodgkin's lymphoma cells [11] . Interestingly, dose-dependent decreases in the total MDM2 and phospho-MDM2 protein levels in the BIIB021-treated cells were observed by Western blotting.…”

“…By binding to the ATP-binding pocket of Hsp90, BIIB021 induces the degradation of Hsp90 client proteins, including HER-2, Akt, and Raf-1, and results in the inhibition of tumor growth [10] . In addition, BIIB021 was found to inhibit the growth of Hodgkin's lymphoma (HL) cells by depleting NF-κB activity and sensitizing the cells to natural killer cell-mediated cytotoxicity [11] . Furthermore, it has been reported that combination therapy using BIIB021 plus radiotherapy or chemotherapy could benefit cancer treatment [12,13] .…”

EBV-positive diffuse large B-cell lymphoma of the elderly

“…81 Notably, Hsp90 inhibitors have been found to suppress NF-kB activity. 82 A CD30-directed antibody-drug conjugate could be a good option given frequent CD30 expression in EBV-positive DLBCL patients. A recent trial of Brentuximab Vedotin in 2 cases of EBV-positive DLBCL did not show promising results, but the small size trial might not be representative.…”

Anti-inflammatory properties and pharmacological induction of Hsp70 after brain injury

“…The best-known purinebased Hsp70-inducer to date is BIIB021 (also named CNF-2024), which has been demonstrated to be a potent Hsp90-inhibitor and is currently in phase 2 clinical studies in its orally administered form Porter et al 2010). One study indicates that BIIB021 may be a potent anti-inflammatory, suppressing the NF-kB pathway in Hodgkin's lymphoma (Boll et al 2009). However, it is yet undetermined whether this or other purine-based compounds produce the same effect in other cell types or disease states or if they can permeate the BBB.…”