The HSP90 inhibitor NVP‐AUY922‐AG inhibits the PI3K and IKK signalling pathways and synergizes with cytarabine in acute myeloid leukaemia cells

Abstract

SummaryHeat shock protein 90 (HSP90; HSP90AA1) is a molecular chaperone involved in signalling pathways for cell proliferation, survival, and cellular adaptation. Inhibitors of HSP90 are being examined as anti-cancer agents, but the critical molecular mechanism(s) of their activity remains unresolved. HSP90 inhibition potentially facilitates the simultaneous targeting of multiple molecules within tumour cells and represents an attractive therapeutic proposition. Here, we investigated HSP90 as a molecular target for acute myeloid leukaemia (AML) using the novel HSP90 inhibitor NVP-AUY922-AG. NVP-AUY922-AG induced dosedependent killing in myeloid cell lines and primary AML blasts. In primary blasts, cell death in response to NVP-AUY922-AG was seen at concentrations almost 2 logs lower than cytarabine (Ara-C) (50% lethal dose = 0Á12 l mol/l AE 0Á28). NVP-AUY922-AG was significantly less toxic to normal bone marrow (P = 0Á02). In vitro response to NVP-AUY922-AG did not correlate with response to Ara-C (r 2 = 0Á0006).NVP-AUY922-AG was highly synergistic with Ara-C in cell lines and in 20/25 of the primary samples tested. NVP-AUY922-AG induced increases in HSP70 expression and depletion of total AKT, IKKa and IKKb in cell lines and primary blasts. This study shows that the novel HSP90 inhibitor NVP-AUY922-AG has significant single agent activity in AML cells and is synergistic with Ara-C.

Hsp90 inhibitor induces KG-1a cell differentiation and apoptosis via Akt/NF-κB signaling

“…Hsp90 is overexpressed in most cancers; pharmacological inhibition of this protein can induce apoptosis in hematologic and other types of tumors (9). In the present study, we demonstrated that the Hsp90 inhibitor SNX-2112 suppressed the proliferation of KG-1a cells and induced their arrest in the G2/M phase and their differentiation and apoptosis in a time-and dose-dependent manner.…”

“…Hsp90 inhibition has been demonstrated to block PI3K and IKK signaling pathways (9). We therefore investigated whether SNX-2112 treatment affected the expression of Akt and IKK by western blotting.…”

“…Most Hsp90 inhibitors exhibit great anti-acute myeloid leukemia effects. The second-generation Hsp90 inhibitor NVP-AUY922-AG was demonstrated to be cytotoxic in myeloid cell lines and primary AML cells (9), and other Hsp90 inhibitors were tested in phase I clinical trials and have been well tolerated in patients with advanced AML (10). SNX-2112 is a novel inhibitor that competitively binds to the N-terminal ATP-binding site of Hsp90 and has shown anticancer activity in vitro and in vivo (3,11).…”

Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic

“…235 Patients who were co-treated with cytarabine exhibited synergetic anti-myeloid effects. 236,237 HDACIs were also able to synergistically enhance 17-AAG activity against leukemic cells, including those expressing FLT3 mutation. 238,239 The mechanisms of resistance to HSP90 inhibition were extensively reviewed by Piper and colleagues.…”

Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease

“…Hsp90, in particular, is involved with the binding of lipopolysaccharide (LPS) to cells and is known to interact with other immune regulating factors including interferon regulatory factor 3, major histocompatibility complex (MHC) maturation, IκB kinase (IKK), multiple toll-like receptors (TLRs) and T cells, along with natural killer (NK) cells 30–34 . Since Hsp90 is involved in the activation of pro-inflammatory cytokines, as was elegantly demonstrated with IL-17 35 and IL-4 36 , a number of Hsp90 inhibitors have been shown to be protective against various inflammatory insults 37–41 . It is also important to note that inflammation has been shown numerous times to be coupled with an increased in Hsp90α specifically 11, 36 , possibly making it an important target for AD treatment.…”