Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Lymphocytic Leukemia

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 15dΔ12,14,PGJ2

Leukemia volume 23, pages 292–304 (2009)Cite this article

Abstract

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in older adults, remains largely incurable and novel treatments are urgently required. We previously reported powerful pro-apoptotic actions of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against Burkitts lymphoma cells. Here, we demonstrate that BEZ and MPA individually, and more potently when combined (BEZ+MPA), induce apoptosis of unsorted and CD19+ve-selected CLL cells and abrogate the pro-proliferative activity of CD40L. This action was tumor cell specific, as the drugs had little impact on normal donor cells. The antiproliferative actions of BEZ+MPA were associated with the generation of reactive oxygen species (ROS), and the proapoptotic actions were associated with the generation of both ROS and mitochondrial superoxide (MSO). BEZ increased prostaglandin D2 (PGD2) synthesis by CLL cells, and treatment with PGD2 and its antineoplastic derivative 15dΔ12,14,PGJ2 recapitulated BEZ-induced antiproliferative and proapoptotic actions. The PGD2 receptor antagonist, BW868C, did not block BEZ or PGD2 activity against CLL cells. The potency of BEZ+MPA against CLL cells mirrored that of chlorambucil, and BEZ+MPA combined with chlorambucil was more potent than either treatment alone. Given the known safety profiles of BEZ and MPA, our data warrant further investigation of their potential as novel therapy for CLL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Ghia P, Ferreri AM, Galigaris-Cappio F . Chronic lymphocytic leukemia. Crit Rev Oncol Hematol 2007; 64: 234–246.

    Article  Google Scholar 

  2. Oscier D, Fegan C, Hillmen P, Illidge T, Johnson S, Maguire P et al. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol 2004; 125: 294–317.

    Article  CAS  Google Scholar 

  3. Kay NE, Rai KR, O'Brien S . Chronic lymphocytic leukemia: current and emerging treatment approaches. Clin Adv Hematol Oncol 2006; 4 (11 Suppl 22): 1–12.

    PubMed  Google Scholar 

  4. Wierda W, O'Brien S, Faderl S, Ferrajoli A, Wang X, Do KA et al. A retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer 2006; 106: 337–345.

    Article  CAS  Google Scholar 

  5. Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4079–4088.

    Article  CAS  Google Scholar 

  6. Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4070–4078.

    Article  CAS  Google Scholar 

  7. Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R . Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev (Online) 2006; 3: CD004270.

    Google Scholar 

  8. Nabhan C, Coutre S, Hillmen P . Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime? Br J Haematol 2007; 136: 379–392.

    Article  Google Scholar 

  9. Fenton SL, Luong QT, Sarafeim A, Mustard KJ, Pound J, Desmond JC et al. Fibrates and medroxyprogesterone acetate induce apoptosis of primary Burkitt's lymphoma cells and cell lines: potential for applying old drugs to a new disease. Leukemia 2003; 17: 568–575.

    Article  CAS  Google Scholar 

  10. Bunce CM, Mountford JC, French PJ, Mole DJ, Durham J, Michell RH et al. 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. Biochimica Et Biophysica Acta 1996; 1311: 189–198.

    Article  Google Scholar 

  11. Desmond JC, Mountford JC, Drayson MT, Walker EA, Hewison M, Ride JP et al. The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs. Cancer Res 2003; 63: 505–512.

    CAS  PubMed  Google Scholar 

  12. Fenton SL, Drayson MT, Hewison M, Vickers E, Brown G, Bunce CM . Clofibric acid: a potential therapeutic agent in AML and MDS. Br J Haematol 1999; 105: 448–451.

    Article  CAS  Google Scholar 

  13. Gagro A, McCloskey N, Challa A, Holder M, Grafton G, Pound JD et al. CD5-positive and CD5-negative human B cells converge to an indistinguishable population on signalling through B-cell receptors and CD40. Immunology 2000; 101: 201–209.

    Article  CAS  Google Scholar 

  14. Scatena R, Bottoni P, Martorana GE, Ferrari F, De Sole P, Rossi C et al. Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of synthetic PPAR-ligands: biochemical and pharmacological implications. Biochem Biophys Res Commun 2004; 319: 967–973.

    Article  CAS  Google Scholar 

  15. Scatena R, Bottoni P, Vincenzoni F, Messana I, Martorana GE, Nocca G et al. Bezafibrate induces a mitochondrial derangement in human cell lines: a PPAR-independent mechanism for a peroxisome proliferator. Chem Res Toxicol 2003; 16: 1440–1447.

    Article  CAS  Google Scholar 

  16. Gao L, Zackert WE, Hasford JJ, Danekis ME, Milne GL, Remmert C et al. Formation of prostaglandins E2 and D2 via the isoprostane pathway: a mechanism for the generation of bioactive prostaglandins independent of cyclooxygenase. J Biol Chem 2003; 278: 28479–28489.

    Article  CAS  Google Scholar 

  17. Ray DM, Akbiyik F, Phipps RP . 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. J Immunol 2006; 177: 5068–5076.

    Article  CAS  Google Scholar 

  18. Chong CR, Sullivan Jr DJ . New uses for old drugs. Nature 2007; 448: 645–646.

    Article  CAS  Google Scholar 

  19. Fenaux P, Wang ZZ, Degos L . Treatment of acute promyelocytic leukemia by retinoids. Curr Top Microbiol Immunol 2007; 313: 101–128.

    CAS  PubMed  Google Scholar 

  20. Chen Z, Zhao WL, Shen ZX, Li JM, Chen SJ, Zhu J et al. Arsenic trioxide and acute promyelocytic leukemia: clinical and biological. Curr Top Microbiol Immunol 2007; 313: 129–144.

    CAS  PubMed  Google Scholar 

  21. Prince HM, Schenkel B, Mileshkin L . An analysis of clinical trials assessing the efficacy and safety of single-agent thalidomide in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma 2007; 48: 46–55.

    Article  CAS  Google Scholar 

  22. Mone AP, Cheney C, Banks AL, Tridandapani S, Mehter N, Guster S et al. Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. Leukemia 2006; 20: 272–279.

    Article  CAS  Google Scholar 

  23. Eucker J, Bangeroth K, Zavrski I, Krebbel H, Zang C, Heider U et al. Ligands of peroxisome proliferator-activated receptor gamma induce apoptosis in multiple myeloma. Anti-Cancer Drugs 2004; 15: 955–960.

    Article  CAS  Google Scholar 

  24. Eucker J, Sterz J, Krebbel H, Zavrski I, Kaiser M, Zang C et al. Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma. Anti-Cancer Drugs 2006; 17: 763–769.

    Article  CAS  Google Scholar 

  25. Higashiyama K, Niiya K, Ozawa T, Hayakawa Y, Fujimaki M, Sakuragawa N . Induction of c-fos protooncogene transcription and apoptosis by delta 12-prostaglandin J2 in human Pl-21 myeloid leukemia and RC-K8 pre-B lymphoma cells. Prostaglandins 1996; 52: 143–156.

    Article  CAS  Google Scholar 

  26. Padilla J, Kaur K, Harris SG, Phipps RP . PPAR-gamma-mediated regulation of normal and malignant B lineage cells. Ann NY Acad Sci 2000; 905: 97–109.

    Article  CAS  Google Scholar 

  27. Ray DM, Bernstein SH, Phipps RP . Human multiple myeloma cells express peroxisome proliferator-activated receptor gamma and undergo apoptosis upon exposure to PPARgamma ligands. Clin Immunol (Orlando, FL) 2004; 113: 203–213.

    Article  CAS  Google Scholar 

  28. Date M, Fukuchi K, Morita S, Takahashi H, Ohura K . 15-Deoxy-delta12,14-prostaglandin J2, a ligand for peroxisome proliferators-activated receptor-gamma, induces apoptosis in human hepatoma cells. Liver Int 2003; 23: 460–466.

    Article  CAS  Google Scholar 

  29. Hayashi N, Nakamori S, Hiraoka N, Tsujie M, Xundi X, Takano T et al. Antitumor effects of peroxisome proliferator activate receptor gamma ligands on anaplastic thyroid carcinoma. Inter J Oncol 2004; 24: 89–95.

    CAS  Google Scholar 

  30. Kondo M, Shibata T, Kumagai T, Osawa T, Shibata N, Kobayashi M et al. 15-Deoxy-Delta(12,14)-prostaglandin J(2): the endogenous electrophile that induces neuronal apoptosis. Proc Nat Acad Sci USA 2002; 99: 7367–7372.

    Article  CAS  Google Scholar 

  31. Lin MS, Chen WC, Bai X, Wang YD . Activation of peroxisome proliferator-activated receptor gamma inhibits cell growth via apoptosis and arrest of the cell cycle in human colorectal cancer. J Dig Dis 2007; 8: 82–88.

    Article  CAS  Google Scholar 

  32. Liu H, Zang C, Fenner MH, Possinger K, Elstner E . PPARgamma ligands and ATRA inhibit the invasion of human breast cancer cells in vitro. Breast Cancer Res Treat 2003; 79: 63–74.

    Article  CAS  Google Scholar 

  33. Morosetti R, Servidei T, Mirabella M, Rutella S, Mangiola A, Maira G et al. The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines. Inter J Oncol 2004; 25: 493–502.

    CAS  Google Scholar 

  34. Nikitakis NG, Siavash H, Hebert C, Reynolds MA, Hamburger AW, Sauk JJ . 15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells. Br J Cancer 2002; 87: 1396–1403.

    Article  CAS  Google Scholar 

  35. Hasegawa H, Yamada Y, Komiyama K, Hayashi M, Ishibashi M, Sunazuka T et al. A novel natural compound, a cycloanthranilylproline-derivative (fuligocandin B), sensitizes leukemia cells to TRAIL-induced apoptosis through 15d-PGJ2 production. Blood 2007; 110: 1664–1674.

    Article  CAS  Google Scholar 

  36. Yoshikuni Y, Chokai S, Ozaki T, Yoshida H, Nakane M, Kuwabara K . Hypolipidemic effect of NS-1 and other related drugs in rhesus monkeys. Atherosclerosis 1988; 74: 149–156.

    Article  CAS  Google Scholar 

  37. Heintel D, Kienle D, Shehata M, Krober A, Kroemer E, Schwarzinger I et al. High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia. Leukemia 2005; 19: 1216–1223.

    Article  CAS  Google Scholar 

  38. Pallasch CP, Schwamb J, Konigs S, Schulz A, Debey S, Kofler D et al. Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells. Leukemia 2008; 22: 585–592.

    Article  CAS  Google Scholar 

  39. Totsuka M, Miyashita Y, Ito Y, Watanabe H, Murano T, Shirai K . Enhancement of preheparin serum lipoprotein lipase mass by bezafibrate administration. Atherosclerosis 2000; 153: 175–179.

    Article  CAS  Google Scholar 

  40. Bentel JM, Birrell SN, Pickering MA, Holds DJ, Horsfall DJ, Tilley WD . Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells. Mol Cell Endocrinol 1999; 154: 11–20.

    Article  CAS  Google Scholar 

  41. Kawaguchi M, Watanabe J, Hamano M, Kamata Y, Arai T, Nishimura Y et al. Medroxyprogesterone acetate stimulates cdk inhibitors, p21 and p27, in endometrial carcinoma cells transfected with progesterone receptor-B cDNA. Eur J Gynaecol Oncol 2006; 27: 33–38.

    CAS  PubMed  Google Scholar 

  42. Poulin R, Baker D, Poirier D, Labrie F . Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells. Breast Cancer Res Treat 1989; 13: 161–172.

    Article  CAS  Google Scholar 

  43. Florio S, Crispino L, Ciarcia R, Vacca G, Pagnini U, de Matteis A et al. MPA increases idarubicin-induced apoptosis in chronic lymphatic leukaemia cells via caspase-3. J Cell Biochem 2003; 89: 747–754.

    Article  CAS  Google Scholar 

  44. Pagnini U, Pacilio C, Florio S, Crispino A, Claudio PP, Giordano A et al. Medroxyprogesterone acetate increases anthracyclines uptake in chronic lymphatic leukemia cells: role of nitric oxide and lipid peroxidation. Anticancer Res 2000; 20 (1A): 33–42.

    CAS  PubMed  Google Scholar 

  45. Zibera C, Gibelli N, Maestri L, Della Cuna GR . Medroxyprogesterone-acetate reverses the MDR phenotype of the CG5-doxorubicin resistant human breast cancer cell line. Anticancer Res 1995; 15: 745–749.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Leukaemia Research Fund UK. CP is the recipient of a BBSRC PhD studentship. We thank Professor Paul Moss for provision of early CLL samples. REH intellectual input, principal laboratory experimentation and manuscript preparation; GP supply and analysis of CLL samples; NJD laboratory experimentation and manuscript preparation; FLK laboratory experimentation and manuscript preparation; JB laboratory experimentation; JD statistical analyses; CP laboratory experimentation; TS laboratory experimentation; MD and CB co-PIs and manuscript preparation. None of the authors have a conflict of interest.

Author information

Authors and Affiliations

  1. University of Birmingham, School of Biosciences, Edgbaston, Birmingham, UK

    R E Hayden, N J Davies, F L Khanim, J Birtwistle, C Pearce, T Sant & C M Bunce

  2. Department of Haematology, Heartlands and Solihull NHS Trust, Bordesley Green East, Birmingham, UK

    G Pratt

  3. Servicio de Hematología Clínica, Hospital de la Santa Creu i Sant Pau Sant Antoni M. Claret, Barcelona, Spain

    J Delgado

  4. Division of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham, UK

    M T Drayson

Authors
  1. R E Hayden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Pratt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N J Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F L Khanim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Birtwistle
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Pearce
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Sant
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M T Drayson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C M Bunce
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C M Bunce.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hayden, R., Pratt, G., Davies, N. et al. 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 15dΔ12,14,PGJ2. Leukemia 23, 292–304 (2009). https://doi.org/10.1038/leu.2008.283

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.283

Keywords

This article is cited by

Search

Advanced search

Quick links