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

• Published in: PloS one Vol. 4; no. 12; p. e8147
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-12-2009; Public Library of Science (PLoS)
• Subjects: 3-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; Acetates; Acetic acid; Acute myeloid leukemia; Aldo-keto reductase; Aldo-Keto Reductase Family 1 Member C3; Antigens, CD34 - metabolism; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Arsenic; Bezafibrate; Bezafibrate - pharmacology; Bezafibrate - therapeutic use; Biotechnology; Cancer therapies; Cell differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Cell lines; Chemotherapy; Cholecalciferol - metabolism; Clinical trials; Deoxyribonucleic acid; Disease; DNA; Drug Screening Assays, Antitumor; Genetics; Geriatrics; Glutathione - metabolism; Hematology; Hematology/Acute Myeloid Leukemia; Hematology/Myelodysplastic Syndrome and Bone Marrow Failure; Hemopoiesis; Humans; Hydroxyprostaglandin Dehydrogenases - antagonists & inhibitors; I-kappa B Proteins - metabolism; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Ligands; Lipid peroxidation; Lipids; Medical prognosis; Medroxyprogesterone; Medroxyprogesterone acetate; Medroxyprogesterone Acetate - pharmacology; Medroxyprogesterone Acetate - therapeutic use; Metabolism; Multiple myeloma; Nonsteroidal anti-inflammatory drugs; Older people; Oncology; Oncology/Hematological Malignancies; Oxidative stress; Oxygen; Patients; Peroxidation; Physiological aspects; PPAR gamma - metabolism; Prostaglandin D2; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Spectrum analysis; Survival; Synthesis; Tumor necrosis factor-TNF; Vitamin A - metabolism; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008147

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.
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.
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.