Oncotarget

Research Papers:

The Hsp90 inhibitor NVP-AUY922-AG inhibits NF-κB signaling, overcomes microenvironmental cytoprotection and is highly synergistic with fludarabine in primary CLL cells

Elisabeth J. Walsby _, Laurence Pearce, Alan K. Burnett, Chris Fegan and Chris Pepper

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Oncotarget. 2012; 3:525-534. https://doi.org/10.18632/oncotarget.491

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Abstract

Elisabeth Walsby1, Lawrence Pearce1, Alan K. Burnett1, Chris Fegan1, Chris Pepper1

1 Department of Haematology, Institute of Cancer and Genetics, Cardiff University, School of Medicine, Cardiff, UK

Received: May 2, 2012; Accepted: May 16, 2012; Published: May 19, 2012;

Keywords: Hsp90, CLL, apoptosis, synergy, NF-κB

Correspondence:

Elisabeth Walsby, email:

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of multiple over-expressed signaling proteins that promote growth and survival in cancer cells. Chronic lymphocytic leukaemia (CLL) is characterized by increased expression of several Hsp90 client proteins making it a potentially susceptible to Hsp90 inhibition. In this study we showed that the novel Hsp90 inhibitor NVP-AUY922-AG was cytotoxic to primary CLL cells in vitro (LD50=0.18µM±0.20). Importantly, its toxicity was preserved under cytoprotective co-culture conditions that rendered fludarabine ineffective. At the molecular level, NVP-AUY922-AG depleted the expression of multiple Hsp90 client proteins including Akt and activators of NF-κB, IKKα and IKKβ. Consistent with this inhibition profile, NVP-AUY922-AG resulted in decreased transcription of the NF-B target genes MCL1, CFLAR, BIRC5. In contrast, fludarabine significantly induced the transcription of MCL1 and BIRC5. Given the anti-apoptotic nature of these genes and the role they play in fludarabine resistance, we considered that the combination of NVP-AUY922-AG with fludarabine might resensitize CLL cells to the effects of fludarabine. In keeping with this hypothesis, the combination of NVP-AUY922-AG and fludarabine was highly synergistic (mean CI=0.110.06) and this synergy was enhanced in co-culture (mean CI=0.06±0.08). Furthermore, the combination maintained the decrease in MCL1, CFLAR and BIRC5 transcription suggesting that the ability of NVP-AUY922-AG to modulate expression of these genes may contribute to the efficacy of this drug under cytoprotective co-culture conditions and for its remarkable synergy with fludarabine. Taken together these findings indicate that Hsp90 inhibition is an attractive therapeutic strategy in CLL.


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