Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia.
<h4>Background</h4>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, thera...
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2009
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oai:doaj.org-article:9636c763c1a443abb133d3874ed803032021-11-25T06:27:34ZCombined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia.1932-620310.1371/journal.pone.0008147https://doaj.org/article/9636c763c1a443abb133d3874ed803032009-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19997560/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Principal findings</h4>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 Delta(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) 11beta -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9alpha11beta-PGF(2alpha). 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.<h4>Significance</h4>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.Farhat L KhanimRachel E HaydenJane BirtwistleAlessia LodiStefano TizianiNicholas J DaviesJon P RideMark R ViantUlrich L GuntherJoanne C MountfordHeinrich SchreweRichard M GreenJim A MurrayMark T DraysonChris M BuncePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 12, p e8147 (2009) |
| institution |
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| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Farhat L Khanim Rachel E Hayden Jane Birtwistle Alessia Lodi Stefano Tiziani Nicholas J Davies Jon P Ride Mark R Viant Ulrich L Gunther Joanne C Mountford Heinrich Schrewe Richard M Green Jim A Murray Mark T Drayson Chris M Bunce Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia. |
| description |
<h4>Background</h4>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.<h4>Principal findings</h4>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 Delta(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) 11beta -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9alpha11beta-PGF(2alpha). 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.<h4>Significance</h4>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 |
article |
| author |
Farhat L Khanim Rachel E Hayden Jane Birtwistle Alessia Lodi Stefano Tiziani Nicholas J Davies Jon P Ride Mark R Viant Ulrich L Gunther Joanne C Mountford Heinrich Schrewe Richard M Green Jim A Murray Mark T Drayson Chris M Bunce |
| author_facet |
Farhat L Khanim Rachel E Hayden Jane Birtwistle Alessia Lodi Stefano Tiziani Nicholas J Davies Jon P Ride Mark R Viant Ulrich L Gunther Joanne C Mountford Heinrich Schrewe Richard M Green Jim A Murray Mark T Drayson Chris M Bunce |
| author_sort |
Farhat L Khanim |
| title |
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_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_sort |
combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/9636c763c1a443abb133d3874ed80303 |
| work_keys_str_mv |
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| _version_ |
1718413696010551296 |