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Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785482/ https://www.ncbi.nlm.nih.gov/pubmed/19997560 http://dx.doi.org/10.1371/journal.pone.0008147 |
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author | Khanim, Farhat L. Hayden, Rachel E. Birtwistle, Jane Lodi, Alessia Tiziani, Stefano Davies, Nicholas J. Ride, Jon P. Viant, Mark R. Gunther, Ulrich L. Mountford, Joanne C. Schrewe, Heinrich Green, Richard M. Murray, Jim A. Drayson, Mark T. Bunce, Chris M. |
author_facet | Khanim, Farhat L. Hayden, Rachel E. Birtwistle, Jane Lodi, Alessia Tiziani, Stefano Davies, Nicholas J. Ride, Jon P. Viant, Mark R. Gunther, Ulrich L. Mountford, Joanne C. Schrewe, Heinrich Green, Richard M. Murray, Jim A. Drayson, Mark T. Bunce, Chris M. |
author_sort | Khanim, Farhat L. |
collection | PubMed |
description | 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 D(2) (PGD(2)) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ(12,14) PGJ(2) (15d-PGJ(2)). BEZ increased PGD(2) synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ(2) by inhibiting the PGD(2) 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9α11β-PGF(2α). 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-PGJ(2). 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-PGJ(2). These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML. |
format | Text |
id | pubmed-2785482 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-27854822009-12-08 Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia Khanim, Farhat L. Hayden, Rachel E. Birtwistle, Jane Lodi, Alessia Tiziani, Stefano Davies, Nicholas J. Ride, Jon P. Viant, Mark R. Gunther, Ulrich L. Mountford, Joanne C. Schrewe, Heinrich Green, Richard M. Murray, Jim A. Drayson, Mark T. Bunce, Chris M. PLoS One Research Article 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 D(2) (PGD(2)) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ(12,14) PGJ(2) (15d-PGJ(2)). BEZ increased PGD(2) synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ(2) by inhibiting the PGD(2) 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9α11β-PGF(2α). 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-PGJ(2). 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-PGJ(2). These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML. Public Library of Science 2009-12-07 /pmc/articles/PMC2785482/ /pubmed/19997560 http://dx.doi.org/10.1371/journal.pone.0008147 Text en Khanim et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Khanim, Farhat L. Hayden, Rachel E. Birtwistle, Jane Lodi, Alessia Tiziani, Stefano Davies, Nicholas J. Ride, Jon P. Viant, Mark R. Gunther, Ulrich L. Mountford, Joanne C. Schrewe, Heinrich Green, Richard M. Murray, Jim A. Drayson, Mark T. Bunce, Chris M. Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia |
title | Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia |
title_full | Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia |
title_fullStr | Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia |
title_full_unstemmed | Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia |
title_short | Combined Bezafibrate and Medroxyprogesterone Acetate: Potential Novel Therapy for Acute Myeloid Leukaemia |
title_sort | combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785482/ https://www.ncbi.nlm.nih.gov/pubmed/19997560 http://dx.doi.org/10.1371/journal.pone.0008147 |
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