Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells

Hampson, Peter, Wang, Keqing, Ersvær, Elisabeth, Mccormack, Emmet, Schüler, Julia, Fiebig, Heinz-herbert, Gjertsen, Bjørn Tore, Bruserud, Øystein and Lord, Janet M. (2014). Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells. Oncoscience, 1 (8), pp. 529-539.

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.

Publication DOI: https://doi.org/10.18632/oncoscience.v1i8
Divisions: Life & Health Sciences > Optometry
Aston Medical School
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Published Date: 2014-08-06
Authors: Hampson, Peter
Wang, Keqing
Ersvær, Elisabeth
Mccormack, Emmet
Schüler, Julia
Fiebig, Heinz-herbert
Gjertsen, Bjørn Tore
Bruserud, Øystein
Lord, Janet M.

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