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Exp Cell Res. 2016 Jan 15;340(2):220-6. doi: 10.1016/j.yexcr.2015.12.017. Epub 2015 Dec 31.

The novel HSP90 inhibitor NVP-AUY922 shows synergistic anti-leukemic activity with cytarabine in vivo.

Author information

1
Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway.
2
Department of Pathology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
3
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway. Electronic address: Skjalgbr@gmail.com.
4
Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0379 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway. Electronic address: antoni.wiedlocha@rr-research.no.

Abstract

HSP90 is a molecular chaperone essential for stability, activity and intracellular sorting of many proteins, including oncoproteins, such as tyrosine kinases, transcription factors and cell cycle regulatory proteins. Therefore, inhibitors of HSP90 are being investigated for their potential as anti-cancer drugs. Here we show that the HSP90 inhibitor NVP-AUY922 induced degradation of the fusion oncoprotein FOP2-FGFR1 in a human acute myeloid leukemia (AML) cell line, KG-1a. Concordantly, downstream signaling cascades, such as STAT1, STAT3 and PLCĪ³ were abrogated. At concentrations that caused FOP2-FGFR1 degradation and signaling abrogation, NVP-AUY922 treatment caused significant cell death and inhibition of proliferation of KG-1a cells in vitro. In an animal model for AML, NVP-AUY922 administrated alone showed no anti-leukemic activity. However, when NVP-AUY922 was administered in combination with cytarabine, the two compounds showed significant synergistic anti-leukemic activity in vivo. Thus NVP-AUY922 and cytarabine combination therapy might be a prospective strategy for AML treatment.

KEYWORDS:

Cytarabine; HSP90; KG-1a leukemia; NVP-AUY922; Tyrosine kinase

PMID:
26748184
DOI:
10.1016/j.yexcr.2015.12.017
[Indexed for MEDLINE]

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