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-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis.


RESULTS
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.


CONCLUSIONS
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.
Khanim
Farhat L
FL
School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
Hayden
Rachel E
RE
Birtwistle
Jane
J
Lodi
Alessia
A
Tiziani
Stefano
S
Davies
Nicholas J
NJ
Ride
Jon P
JP
Viant
Mark R
MR
Gunther
Ulrich L
UL
Mountford
Joanne C
JC
Schrewe
Heinrich
H
Green
Richard M
RM
Murray
Jim A
JA
Drayson
Mark T
MT
Bunce
Chris M
CM
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000074425:Aldo-Keto Reductase Family 1 Member C3; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001629:Bezafibrate / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors; D020672:I-kappa B Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology / Q000627:therapeutic use*; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D018952:Antigens, CD34; D020672:I-kappa B Proteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D014801:Vitamin A; D002762:Cholecalciferol; D017258:Medroxyprogesterone Acetate; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D005978:Glutathione; D015230:Prostaglandin D2; D001629:Bezafibrate