Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells
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https://doi.org/10.18632/oncoscience.71
Peter Hampson1, Keqing Wang2, Keqing Wang2, Elisabeth Ersvær3, Emmet McCormack3, Julia Schüler4, Heinz-Herbert Fiebig4, Bjørn Tore Gjertsen3, Øystein Bruserud3, Janet M. Lord1
1 School of Immunity and Infection, University of Birmingham, Birmingham, B15 2TT, UK
2 Department of Biosciences, University of Aston, Birmingham, B4 7ET
3 Institute of Medicine, University of Bergen, Bergen, NO-5020, Norway
4 Oncotest GmbH, 79801 Freiburg, Germany
Correspondence:
Peter Hampson, email:
Keywords: AML, PEP005, PKC, anti-apoptotic, xenograft model
Received: June 24, 2014 Accepted: August 2, 2014 Published: August 6, 2014
Abstract
We showed previously that PEP005 induced apoptosis in leukaemic cell lines and blasts from patients with acute myeloid leukaemia (AML). Here we assess the anti-leukeamic effects of PEP005 in vivo and determine the mechanism of resistance of PEP005 non-responsive cells. We used 2 human xenograft mouse models of AML to assess the anti-leukaemic effects of PEP005 in vivo. Expression microarray analysis of primary AML blasts following treatment with PEP005 was used to determine patterns of gene expression that conferred resistance. PEP005 significantly reduced tumour burden in two human leukaemia mouse xenograft models. We also assessed responsiveness of 33 AML samples to PEP005, with 78% of the samples entering apoptosis at 100nM. Resistance to PEP005 was not restricted to a particular AML subtype. Expression microarray analysis of resistant samples following treatment with PEP005 revealed a significant up regulation of the anti-apoptotic genes Bcl-2A1, Mcl-1, and PHLDA1 which was verified using RT-PCR. We conclude that PEP005 shows broad efficacy against AML subtypes and that up regulation of anti-apoptotic genes underlies resistance to this agent and could be used to screen for patients unlikely to benefit from a therapeutic regime involving PEP005.
