Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia

Khanim, F.L. et al. (2009) Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia. PLoS ONE, 4(12), e8147. (doi:10.1371/journal.pone.0008147)

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Abstract

Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis. Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D2 (PGD2) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ12,14 PGJ2 (15d-PGJ2). BEZ increased PGD2 synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ2 by inhibiting the PGD2 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD2 to 9α11β-PGF2α. B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ2. Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors. Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ2. These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML.

Item Type:Articles
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.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mountford, Dr Joanne
Authors: Khanim, F.L., Hayden, R.E., Birtwistle, J., Lodi, A., Tiziani, S., Davies, N.J., Ride, J.P., Viant, M.R., Gunther, U.L., Mountford, J.C., Schrewe, H., Green, R., Murray, J.A., Drayson, M.T., and Bunce, C.M.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Published Online:01 January 2009
Copyright Holders:© 2009 Khanim et al.
First Published:First published in PLoS ONE 2009 4(12): e8147
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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