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

Elisabeth J Walsby; Michelle Lazenby; Chris J Pepper; Steven Knapper; Alan K Burnett

doi:10.1111/bjh.12215

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

Br J Haematol. 2013 Apr;161(1):57-67. doi: 10.1111/bjh.12215. Epub 2013 Jan 29.

Authors

Elisabeth J Walsby¹, Michelle Lazenby, Chris J Pepper, Steven Knapper, Alan K Burnett

Affiliation

¹ Cardiff Experimental Cancer Medicine Centre, Institute of Cancer and Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK. [email protected]

PMID: 23356405
DOI: 10.1111/bjh.12215

Abstract

Heat 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 dose-dependent 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 = 0·12 μ mol/l ± 0·28). NVP-AUY922-AG was significantly less toxic to normal bone marrow (P = 0·02). In vitro response to NVP-AUY922-AG did not correlate with response to Ara-C (r(2) = 0·0006). 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, IKKα and IKKβ 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.

MeSH terms

Adult
Aged
Aged, 80 and over
Annexin A5 / metabolism
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis / drug effects
Caspase 3 / metabolism
Cytarabine / administration & dosage
Cytarabine / pharmacology
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor / methods
Drug Synergism
Female
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
I-kappa B Kinase / drug effects
I-kappa B Kinase / metabolism
Isoxazoles / administration & dosage
Isoxazoles / pharmacology*
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Male
Middle Aged
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / metabolism
Phosphatidylinositol 3-Kinases / drug effects
Phosphatidylinositol 3-Kinases / metabolism
Resorcinols / administration & dosage
Resorcinols / pharmacology*
Signal Transduction / drug effects
Tumor Cells, Cultured / drug effects
Young Adult

Substances

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
Annexin A5
Antineoplastic Agents
HSP90 Heat-Shock Proteins
Isoxazoles
Neoplasm Proteins
Resorcinols
Cytarabine
Phosphatidylinositol 3-Kinases
I-kappa B Kinase
Caspase 3