Skip to main content
Article thumbnail
Location of Repository

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

By F.L. Khanim, R.E. Hayden, J. Birtwistle, A. Lodi, S. Tiziani, N.J. Davies, J.P. Ride, M.R. Viant, U.L. Gunther, J.C. Mountford, H. Schrewe, R. Green, J.A. Murray, M.T. Drayson and C.M. Bunce

Abstract

<b>Background</b>: 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.\ud \ud <b>Principal Findings</b>: 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.\ud \ud <b>Significance</b>: 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

Topics: RC0254
Publisher: Public Library of Science
Year: 2009
OAI identifier: oai:eprints.gla.ac.uk:25992
Provided by: Enlighten

Suggested articles

Citations

  1. (1995). 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.
  2. (2000). 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway.
  3. (2002). 15-deoxy-delta 12,14-prostaglandin J2. A prostaglandin D2 metabolite generated during inflammatory processes.
  4. (2009). 15-Deoxy{Delta}12,14-prostaglandin J2 inhibits HIV-1 transactivating protein, Tat, through covalent modification.
  5. (2002). 15-DeoxyDelta(12,14)-prostaglandin J(2): the endogenous electrophile that induces neuronal apoptosis.
  6. (2003). 15-Deoxydelta12,14-prostaglandin J2, a ligand for peroxisome proliferators-activated receptor-gamma, induces apoptosis in human hepatoma cells.
  7. (2002). 15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells.
  8. (2005). 15d-PGJ2: the anti-inflammatory prostaglandin?
  9. (2007). A novel natural compound, a cycloanthranilylproline derivative (Fuligocandin B), sensitizes leukemia cells to apoptosis induced by tumor necrosis factor related apoptosis-inducing ligand (TRAIL) through 15-deoxy-Delta 12, 14 prostaglandin J2 production.
  10. (1995). A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation.
  11. (2008). Accumulation of 15-deoxydelta(12,14)-prostaglandin J2 adduct formation with Keap1 over time: effects on potency for intracellular antioxidant defence induction.
  12. (2007). Activation of peroxisome proliferator-activated receptor gamma inhibits cell growth via apoptosis and arrest of the cell cycle in human colorectal cancer.
  13. (2007). Acute myeloid leukemia and myelodysplastic syndromes in older patients.
  14. (2008). Acute myeloid leukemia in the elderly: conventional and novel treatment approaches.
  15. (2004). Acute promyelocytic leukemia as a paradigm for targeted therapy.
  16. (2000). Antiinflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.
  17. (2004). Antitumor effects of peroxisome proliferator activate receptor gamma ligands on anaplastic thyroid carcinoma.
  18. (2001). Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial.
  19. (1999). Bezafibrate as differentiating factor of human myeloid leukemia cells.
  20. (2003). Bezafibrate induces a mitochondrial derangement in human cell lines: a PPARindependent mechanism for a peroxisome proliferator.
  21. (1999). Clofibric acid: a potential therapeutic agent in AML and MDS.
  22. (2004). Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin.
  23. (2007). Cyclopentenone prostaglandin, 15-deoxy-Delta12,14-PGJ2, is metabolized by HepG2 cells via conjugation with glutathione.
  24. (2007). Direct evidence for the covalent modification of glutathione-S-transferase P1-1 by electrophilic prostaglandins: implications for enzyme inactivation and cell survival.
  25. (2009). Downregulation of hTERT expression plays an important role in 15-deoxyDelta12,14-prostaglandin J2-induced apoptosis in cancer cells.
  26. (2004). Drug repositioning: identifying and developing new uses for existing drugs.
  27. (2005). Drug therapy for acute myeloid leukemia.
  28. (2003). Fibrates and medroxyprogesterone acetate induce apoptosis of primary Burkitt’s lymphoma cells and cell lines: potential for applying old drugs to a new disease.
  29. (2003). Formation of prostaglandins E2 and D2 via the isoprostane pathway: a mechanism for the generation of bioactive prostaglandins independent of cyclooxygenase.
  30. (2002). Human colorectal cancer cells efficiently conjugate the cyclopentenone prostaglandin, prostaglandin J(2), to glutathione. Biochim Biophys Acta 1584: 37–45.
  31. (1998). Identification of a retinoic acid responsive aldoketoreductase expressed in HL60 leukaemic cells.
  32. (2007). Identification of actin as a 15-deoxy-Delta12,14-prostaglandin J2 target in neuroblastoma cells: mass spectrometric, computational, and functional approaches to investigate the effect on cytoskeletal derangement.
  33. (2006). Identification of novel protein targets for modification by 15-deoxy-Delta12,14-prostaglandin J2 in mesangial cells reveals multiple interactions with the cytoskeleton.
  34. (2007). Induction of DNA strand breaks and oxidative stress in HeLa cells by ethanol is dependent on CYP2E1 expression.
  35. (2006). Induction of the permeability transition and cytochrome c release by 15-deoxy-Delta12,14-prostaglandin J2 in mitochondria.
  36. (2007). Insights into oxidative stress: the isoprostanes.
  37. (1996). Intracellular glutathione level modulates the induction of apoptosis by delta 12-prostaglandin J2.
  38. (2008). Is the focus moving toward a combination of targeted drugs?
  39. (2009). Metabolomic profiling of drug responses in acute myeloid leukaemia cell lines.
  40. (2004). Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of synthetic PPAR-ligands: biochemical and pharmacological implications.
  41. (2007). Modification and activation of Ras proteins by electrophilic prostanoids with different structure are site-selective.
  42. (2003). Molecular basis for the direct inhibition of AP-1 DNA binding by 15-deoxy-Delta 12,14-prostaglandin J2.
  43. (2007). New uses for old drugs.
  44. (2006). Nonezymatic formation of succinate in mitochondria under oxidative stress.
  45. (1995). Potentiating effects of clofibric acid on the differentiation of HL-60 human promyelocytic leukemia cells induced by retinoids.
  46. (1996). Potentiation of myeloid differentiation by anti-inflammatory agents, by steroids and by retinoic acid involves a single intracellular target, probably an enzyme of the aldoketoreductase family.
  47. (1995). Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1.
  48. (2006). Prostanoids with cyclopentenone structure as tools for the characterization of electrophilic lipid-protein interactomes.
  49. (1985). Purification and properties of 3 alpha-hydroxysteroid dehydrogenase from rat brain cytosol. Inhibition by nonsteroidal anti-inflammatory drugs and progestins.
  50. (2006). Reactive oxygen species in cancer cells: live by the sword, die by the sword.
  51. (2006). Structural basis of the multispecificity demonstrated by 17beta-hydroxysteroid dehydrogenase types 1 and 5.
  52. (2008). Thalidomide in multiple myeloma–clinical trials and aspects of drug metabolism and toxicity.
  53. (2009). The aldo-keto reductase AKR1C3 contributes to 7,12-dimethylbenz(a)anthracene3,4-dihydrodiol mediated oxidative DNA damage in myeloid cells: implications for leukemogenesis.
  54. (2003). The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenasedependent antineoplastic actions of nonsteroidal anti-inflammatory drugs.
  55. (1988). The biology and pharmacology of PGD2.
  56. (2005). The cyclopentenone (A2/J2) isoprostanes–unique, highly reactive products of arachidonate peroxidation.
  57. (2008). The expanding role of arsenic in acute promyelocytic leukemia.
  58. (2009). The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.
  59. (2006). The peroxisome proliferator-activated receptor gamma (PPARgamma) ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARgamma-independent mechanisms.
  60. (2004). The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines.
  61. (2007). The tricarboxylic acid cycle, an ancient metabolic network with a novel twist.
  62. (2008). Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years.
  63. (2008). Translation of the Philadelphia chromosome into therapy for CML.
  64. (2006). Treatment decisionmaking for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches.
  65. (2006). Treatment of older patients with acute myeloid leukemia–new agents.
  66. (2009). Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dDelta12,14,PGJ2.
  67. (2007). Valproic acid for the treatment of myeloid malignancies.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.