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PPAR Research
Volume 2008 (2008), Article ID 834612, 18 pages
http://dx.doi.org/10.1155/2008/834612
Review Article

Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies

1Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
2Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
3Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
4Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
5The Lymphoma Biology Program of James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
6The Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA

Received 17 March 2008; Accepted 21 April 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Tatiana M. Garcia-Bates et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. O. Braissant, F. Foufelle, C. Scotto, M. Dauça, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996. View at Publisher · View at Google Scholar
  2. S. K. Das and R. Chakrabarti, “Role of PPAR in cardiovascular diseases,” Recent Patents on Cardiovascular Drug Discovery, vol. 1, no. 2, pp. 193–209, 2006. View at Google Scholar
  3. B. Staels and J.-C. Fruchart, “Therapeutic roles of peroxisome proliferator-activated receptor agonists,” Diabetes, vol. 54, no. 8, pp. 2460–2470, 2005. View at Publisher · View at Google Scholar
  4. C. E. Quinn, P. K. Hamilton, C. J. Lockhart, and G. E. McVeigh, “Thiazolidinediones: effects on insulin resistance and the cardiovascular system,” British Journal of Pharmacology, vol. 153, no. 4, pp. 636–645, 2008. View at Publisher · View at Google Scholar
  5. M. Bajaj, S. Suraamornkul, L. J. Hardies, L. Glass, N. Musi, and R. A. DeFronzo, “Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus,” Diabetologia, vol. 50, no. 8, pp. 1723–1731, 2007. View at Publisher · View at Google Scholar
  6. A. M. Sharma and B. Staels, “Review: peroxisome proliferator-activated receptor γ and adipose tissue—understanding obesity-related changes in regulation of lipid and glucose metabolism,” Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 2, pp. 386–395, 2007. View at Publisher · View at Google Scholar
  7. A. Krishnan, S. A. Nair, and M. R. Pillai, “Biology of PPARγ in cancer: a critical review on existing lacunae,” Current Molecular Medicine, vol. 7, no. 6, pp. 532–540, 2007. View at Publisher · View at Google Scholar
  8. H. A. Burgess, L. E. Daugherty, T. H. Thatcher et al., “PPAR? agonists inhibit TGF-ß induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis,” American Journal of Physiology, vol. 288, no. 6, pp. L1146–L1153, 2005. View at Publisher · View at Google Scholar
  9. J. E. Milam, V. G. Keshamouni, S. H. Phan et al., “PPAR-? agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis,” American Journal of Physiology, vol. 294, p. L891. View at Publisher · View at Google Scholar
  10. D. S. Straus and C. K. Glass, “Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms,” Trends in Immunology, vol. 28, no. 12, pp. 551–558, 2007. View at Publisher · View at Google Scholar
  11. M. François, P. Richette, L. Tsagris et al., “Peroxisome proliferator-activated receptor-? down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element,” Journal of Biological Chemistry, vol. 279, no. 27, pp. 28411–28418, 2004. View at Publisher · View at Google Scholar
  12. V. G. Keshamouni, D. A. Arenberg, R. C. Reddy, M. J. Newstead, S. Anthwal, and T. J. Standiford, “PPAR-γ activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer,” Neoplasia, vol. 7, no. 3, pp. 294–301, 2005. View at Publisher · View at Google Scholar
  13. L. H. Wang, X. Y. Yang, X. Zhang, and W. L. Farrar, “Nuclear receptors as negative modulators of STAT3 in multiple myeloma,” Cell Cycle, vol. 4, no. 2, pp. 242–245, 2005. View at Google Scholar
  14. B. A. Beamer, C. Negri, C.-J. Yen et al., “Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR?) gene,” Biochemical and Biophysical Research Communications, vol. 233, no. 3, pp. 756–759, 1997. View at Publisher · View at Google Scholar
  15. C. K. Glass and S. Ogawa, “Combinatorial roles of nuclear receptors in inflammation and immunity,” Nature Reviews Immunology, vol. 6, no. 1, pp. 44–55, 2006. View at Publisher · View at Google Scholar
  16. M. Ricote and C. K. Glass, “PPARs and molecular mechanisms of transrepression,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 926–935, 2007. View at Publisher · View at Google Scholar
  17. L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPAR? gene,” Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997. View at Publisher · View at Google Scholar
  18. L. Fajas, J.-C. Fruchart, and J. Auwerx, “PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter,” FEBS Letters, vol. 438, no. 1-2, pp. 55–60, 1998. View at Publisher · View at Google Scholar
  19. H. Sundvold and S. Lien, “Identification of a novel peroxisome proliferator-activated receptor (PPAR) γ promoter in man and transactivation by the nuclear receptor RORα1,” Biochemical and Biophysical Research Communications, vol. 287, no. 2, pp. 383–390, 2001. View at Publisher · View at Google Scholar
  20. Y. Chen, A. R. Jimenez, and J. D. Medh, “Identification and regulation of novel PPAR-γ splice variants in human THP-1 macrophages,” Biochimica et Biophysica Acta, vol. 1759, no. 1-2, pp. 32–43, 2006. View at Publisher · View at Google Scholar
  21. T. Omi, B. Brenig, Š. Špilar Kramer, S. Iwamoto, G. Stranzinger, and S. Neuenschwander, “Identification and characterization of novel peroxisome proliferator-activated receptor-gamma (PPAR-γ) transcriptional variants in pig and human,” Journal of Animal Breeding and Genetics, vol. 122, supplement 1, pp. 45–53, 2005. View at Publisher · View at Google Scholar
  22. H. J. Kim, I. S. Woo, E. S. Kang et al., “Identification of a truncated alternative splicing variant of human PPAR?1 that exhibits dominant negative activity,” Biochemical and Biophysical Research Communications, vol. 347, no. 3, pp. 698–706, 2006. View at Publisher · View at Google Scholar
  23. L. Sabatino, A. Casamassimi, G. Peluso et al., “A novel peroxisome proliferator-activated receptor ? isoform with dominant negative activity generated by alternative splicing,” Journal of Biological Chemistry, vol. 280, no. 28, pp. 26517–26525, 2005. View at Publisher · View at Google Scholar
  24. G. Occhi, N. Albiger, S. Berlucchi et al., “Peroxisome proliferator-activated receptor ? in the human pituitary gland: expression and splicing pattern in adenomas versus normal pituitary,” Journal of Neuroendocrinology, vol. 19, no. 7, pp. 552–559, 2007. View at Publisher · View at Google Scholar
  25. T. Wang, J. Xu, X. Yu, R. Yang, and Z. C. Han, “Peroxisome proliferator-activated receptor γ in malignant diseases,” Critical Reviews in Oncology/Hematology, vol. 58, no. 1, pp. 1–14, 2006. View at Publisher · View at Google Scholar
  26. C. Grommes, G. E. Landreth, and M. T. Heneka, “Antineoplastic effects of peroxisome proliferator-activated receptor γ agonists,” The Lancet Oncology, vol. 5, no. 7, pp. 419–429, 2004. View at Publisher · View at Google Scholar
  27. M.-B. Debril, J.-P. Renaud, L. Fajas, and J. Auwerx, “The pleiotropic functions of peroxisome proliferator-activated receptor γ,” Journal of Molecular Medicine, vol. 79, no. 1, pp. 30–47, 2001. View at Publisher · View at Google Scholar
  28. T. G. Kroll, P. Sarraf, L. Pecciarini et al., “PAX8-PPAR?1 fusion oncogene in human thyroid carcinoma,” Science, vol. 289, no. 5484, pp. 1357–1360, 2000. View at Publisher · View at Google Scholar
  29. H. Sasaki, M. Tanahashi, H. Yukiue et al., “Decreased perioxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer,” Lung Cancer, vol. 36, no. 1, pp. 71–76, 2002. View at Publisher · View at Google Scholar
  30. K. A. Burns and J. P. Vanden Heuvel, “Modulation of PPAR activity via phosphorylation,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 952–960, 2007. View at Publisher · View at Google Scholar
  31. E. Burgermeister, D. Chuderland, T. Hanoch, M. Meyer, M. Liscovitch, and R. Seger, “Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor γ,” Molecular and Cellular Biology, vol. 27, no. 3, pp. 803–817, 2007. View at Publisher · View at Google Scholar
  32. B. Relic, V. Benoit, N. Franchimont et al., “Peroxisome proliferator-activated receptor-?1 is dephosphorylated and degraded during BAY 11-7085-induced synovial fibroblast apoptosis,” Journal of Biological Chemistry, vol. 281, no. 32, pp. 22597–22604, 2006. View at Publisher · View at Google Scholar
  33. E. Burgermeister and R. Seger, “MAPK kinases as nucleo-cytoplasmic shuttles for PPARγ,” Cell Cycle, vol. 6, no. 13, pp. 1539–1548, 2007. View at Google Scholar
  34. Z. E. Floyd and J. M. Stephens, “Interferon-γ-mediated activation and ubiquitin-proteasome-dependent degradation of PPARγ in adipocytes,” Journal of Biological Chemistry, vol. 277, no. 6, pp. 4062–4068, 2002. View at Publisher · View at Google Scholar
  35. S. Hauser, G. Adelmant, P. Sarraf, H. M. Wright, E. Mueller, and B. M. Spiegelman, “Degradation of the peroxisome proliferator-activated receptor γ is linked to ligand-dependent activation,” Journal of Biological Chemistry, vol. 275, no. 24, pp. 18527–18533, 2000. View at Publisher · View at Google Scholar
  36. M. Akaike, W. Che, N.-L. Marmarosh et al., “The hinge-helix 1 region of peroxisome proliferator-activated receptor ?1 (PPAR?1) mediates interaction with extracellular signal-regulated kinase 5 and PPAR?1 transcriptional activation: involvement in flow-induced PPAR? activation in endothelial cells,” Molecular and Cellular Biology, vol. 24, no. 19, pp. 8691–8704, 2004. View at Publisher · View at Google Scholar
  37. G. Pascual and C. K. Glass, “Nuclear receptors versus inflammation: mechanisms of transrepression,” Trends in Endocrinology & Metabolism, vol. 17, no. 8, pp. 321–327, 2006. View at Publisher · View at Google Scholar
  38. D. Yamashita, T. Yamaguchi, M. Shimizu, N. Nakata, F. Hirose, and T. Osumi, “The transactivating function of peroxisome proliferator-activated receptor γ is negatively regulated by SUMO conjugation in the amino-terminal domain,” Genes to Cells, vol. 9, no. 11, pp. 1017–1029, 2004. View at Publisher · View at Google Scholar
  39. T. Ohshima, H. Koga, and K. Shimotahno, “Transcriptional activity of peroxisome proliferator-activated receptor γ is modulated by SUMO-1 modification,” Journal of Biological Chemistry, vol. 279, no. 28, pp. 29551–29557, 2004. View at Publisher · View at Google Scholar
  40. Z. E. Floyd and J. M. Stephens, “Control of peroxisome proliferator-activated receptor γ2 stability and activity by SUMOylation,” Obesity Research, vol. 12, no. 6, pp. 921–928, 2004. View at Publisher · View at Google Scholar
  41. S. J. Choi, S. S. Chung, E. J. Rho et al., “Negative modulation of RXRa transcriptional activity by small ubiquitin-related modifier (SUMO) modification and its reversal by SUMO-specific protease SUSP1,” Journal of Biological Chemistry, vol. 281, no. 41, pp. 30669–30677, 2006. View at Publisher · View at Google Scholar
  42. H. D. Ulrich, “Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest,” Trends in Cell Biology, vol. 15, no. 10, pp. 525–532, 2005. View at Publisher · View at Google Scholar
  43. G. Gill, “Something about SUMO inhibits transcription,” Current Opinion in Genetics & Development, vol. 15, no. 5, pp. 536–541, 2005. View at Publisher · View at Google Scholar
  44. R. T. Hay, “SUMO: a history of modification,” Molecular Cell, vol. 18, no. 1, pp. 1–12, 2005. View at Publisher · View at Google Scholar
  45. H. D. Ulrich, “SUMO modification: wrestling with protein conformation,” Current Biology, vol. 15, no. 7, pp. R257–R259, 2005. View at Publisher · View at Google Scholar
  46. D. Alarcon-Vargas and Z. Ronai, “SUMO in cancer—wrestlers wanted,” Cancer Biology & Therapy, vol. 1, no. 3, pp. 237–242, 2002. View at Google Scholar
  47. K. I. Kim and S. H. Baek, “SUMOylation code in cancer development and metastasis,” Molecules and Cells, vol. 22, no. 3, pp. 247–253, 2006. View at Google Scholar
  48. C. Ulivieri and C. T. Baldari, “The potential of peroxisome proliferator-activated receptor γ (PPARγ) ligands in the treatment of hematological malignancies,” Mini Reviews in Medicinal Chemistry, vol. 7, no. 9, pp. 877–887, 2007. View at Publisher · View at Google Scholar
  49. L. Gelman, J. N. Feige, and B. Desvergne, “Molecular basis of selective PPARγ modulation for the treatment of type 2 diabetes,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 1094–1107, 2007. View at Publisher · View at Google Scholar
  50. T. M. McIntyre, A. V. Pontsler, A. R. Silva et al., “Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPAR? agonist,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 1, pp. 131–136, 2003. View at Publisher · View at Google Scholar
  51. F. J. Schopfer, Y. Lin, P. R. S. Baker et al., “Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor ? ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2340–2345, 2005. View at Publisher · View at Google Scholar
  52. T. M. Willson, P. J. Brown, D. D. Sternbach, and B. R. Henke, “The PPARs: from orphan receptors to drug discovery,” Journal of Medicinal Chemistry, vol. 43, no. 4, pp. 527–550, 2000. View at Publisher · View at Google Scholar
  53. B. M. Forman, P. Tontonoz, J. Chen, R. P. Brun, B. M. Spiegelman, and R. M. Evans, “15-deoxy-Δ12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ,” Cell, vol. 83, no. 5, pp. 803–812, 1995. View at Publisher · View at Google Scholar
  54. S. A. Kliewer, J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann, “A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation,” Cell, vol. 83, no. 5, pp. 813–819, 1995. View at Publisher · View at Google Scholar
  55. J. Wigren, S. Surapureddi, A. G. Olsson, C. K. Glass, S. Hammarström, and M. Söderström, “Differential recruitment of the coactivator proteins CREB-binding protein and steroid receptor coactivator-1 to peroxisome proliferator-activated receptor gamma/9-cis-retinoic acid receptor heterodimers by ligands present in oxidized low-density lipoprotein,” Journal of Endocrinology, vol. 177, no. 2, pp. 207–214, 2003. View at Publisher · View at Google Scholar
  56. S. E. Feldon, C. W. O'Loughlin, D. M. Ray, S. Landskroner-Eiger, K. E. Seweryniak, and R. P. Phipps, “Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes,” The American Journal of Pathology, vol. 169, no. 4, pp. 1183–1193, 2006. View at Publisher · View at Google Scholar
  57. M. Söderström, J. Wigren, S. Surapureddi, C. K. Glass, and S. Hammarstrom, “Novel prostaglandin D2-derived activators of peroxisome proliferator-activated receptor-γ are formed in macrophage cell cultures,” Biochimica et Biophysica Acta, vol. 1631, no. 1, pp. 35–41, 2003. View at Publisher · View at Google Scholar
  58. J. Kim, P. Yang, M. Suraokar et al., “Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products,” Cancer Research, vol. 65, no. 14, pp. 6189–6198, 2005. View at Publisher · View at Google Scholar
  59. M. Fukushima, “Biological activities and mechanisms of action of PGJ2 and related compounds: an update,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 47, no. 1, pp. 1–12, 1992. View at Publisher · View at Google Scholar
  60. F. A. Fitzpatrick and M. A. Wynalda, “Albumin-catalyzed metabolism of prostaglandin D2. Identification of products formed in vitro,” The Journal of Biological Chemistry, vol. 258, no. 19, pp. 11713–11718, 1983. View at Google Scholar
  61. D. M. Ray, S. L. Spinelli, J. J. O'Brien, N. Blumberg, and R. P. Phipps, “Platelets as a novel target for PPARγ ligands: implications for inflammation, diabetes, and cardiovascular disease,” BioDrugs, vol. 20, no. 4, pp. 231–241, 2006. View at Publisher · View at Google Scholar
  62. J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPAR γ),” The Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995. View at Publisher · View at Google Scholar
  63. C. Zang, H. Liu, M. Waechter et al., “Dual PPARa/? ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines,” Cell Cycle, vol. 5, no. 19, pp. 2237–2243, 2006. View at Google Scholar
  64. C. Qin, D. Morrow, J. Stewart et al., “A new class of peroxisome proliferator-activated receptor ? (PPAR?) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes,” Molecular Cancer Therapeutics, vol. 3, no. 3, pp. 247–260, 2004. View at Google Scholar
  65. K. L. Houseknecht, B. M. Cole, and P. J. Steele, “Peroxisome proliferator-activated receptor gamma (PPARγ) and its ligands: a review,” Domestic Animal Endocrinology, vol. 22, no. 1, pp. 1–23, 2002. View at Publisher · View at Google Scholar
  66. Y. Wang, W. W. Porter, N. Suh et al., “A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor ?,” Molecular Endocrinology, vol. 14, no. 10, pp. 1550–1556, 2000. View at Publisher · View at Google Scholar
  67. T. Honda, Y. Honda, F. G. Favaloro Jr. et al., “A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production,” Bioorganic & Medicinal Chemistry Letters, vol. 12, no. 7, pp. 1027–1030, 2002. View at Publisher · View at Google Scholar
  68. K. Liby, D. B. Royce, C. R. Williams et al., “The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice,” Cancer Research, vol. 67, no. 6, pp. 2414–2419, 2007. View at Publisher · View at Google Scholar
  69. D. Hong, R. Kurzrock, J. G. Supko, D. Lawrence, J. Wheeler, and B. J. Dezube, “Phase I trial with a novel orally administered synthetic triterpenoid RTA 402 (CDDO­Me) in patients with solid tumors and lymphoid malignancies,” in Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, p. 188, American Association for Cancer Research, San Francisco, Calif, USA, October 2007.
  70. Y. Guan, C. Hao, D. R. Cha et al., “Thiazolidinediones expand body fluid volume through PPAR? stimulation of ENaC-mediated renal salt absorption,” Nature Medicine, vol. 11, no. 8, pp. 861–866, 2005. View at Publisher · View at Google Scholar
  71. H. E. Lebovitz, “Differentiating members of the thiazolidinedione class: a focus on safety,” Diabetes/Metabolism Research and Reviews, vol. 18, supplement 2, pp. S23–S29, 2002. View at Publisher · View at Google Scholar
  72. V. Sood, K. Colleran, and M. R. Burge, “Thiazolidinediones: a comparative review of approved uses,” Diabetes Technology & Therapeutics, vol. 2, no. 3, pp. 429–440, 2000. View at Publisher · View at Google Scholar
  73. R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-?,” Nature, vol. 395, no. 6698, pp. 137–143, 1998. View at Publisher · View at Google Scholar
  74. F. Zhang, B. E. Lavan, and F. M. Gregoire, “Selective modulators of PPAR-γ activity: molecular aspects related to obesity and side-effects,” PPAR Research, vol. 2007, Article ID 32696, 7 pages, 2007. View at Publisher · View at Google Scholar
  75. H. E. Xu, M. H. Lambert, V. G. Montana et al., “Molecular recognition of fatty acids by peroxisome proliferator-activated receptors,” Molecular Cell, vol. 3, no. 3, pp. 397–403, 1999. View at Publisher · View at Google Scholar
  76. Y. Li, M. H. Lambert, and H. E. Xu, “Activation of nuclear receptors: a perspective from structural genomics,” Structure, vol. 11, no. 7, pp. 741–746, 2003. View at Publisher · View at Google Scholar
  77. J. L. Oberfield, J. L. Collins, C. P. Holmes et al., “A peroxisome proliferator-activated receptor ? ligand inhibits adipocyte differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 11, pp. 6102–6106, 1999. View at Publisher · View at Google Scholar
  78. Y. Wu, W. W. Chin, Y. Wang, and T. P. Burris, “Ligand and coactivator identity determines the requirement of the charge clamp for coactivation of the peroxisome proliferator-activated receptor γ,” The Journal of Biological Chemistry, vol. 278, no. 10, pp. 8637–8644, 2003. View at Publisher · View at Google Scholar
  79. S. Rocchi, F. Picard, J. Vamecq et al., “A unique PPAR? ligand with potent insulin-sensitizing yet weak adipogenic activity,” Molecular Cell, vol. 8, no. 4, pp. 737–747, 2001. View at Publisher · View at Google Scholar
  80. S. M. Rangwala and M. A. Lazar, “The dawn of the SPPARMs?” Science's STKE, vol. 2002, no. 121, p. pe9, 2002. View at Publisher · View at Google Scholar
  81. T.-A. Cock, S. M. Houten, and J. Auwerx, “Peroxisome proliferator-activated receptor-γ: too much of a good thing causes harm,” EMBO Reports, vol. 5, no. 2, pp. 142–147, 2004. View at Publisher · View at Google Scholar
  82. A. R. Miller and G. J. Etgen, “Novel peroxisome proliferator-activated receptor ligands for type 2 diabetes and the metabolic syndrome,” Expert Opinion on Investigational Drugs, vol. 12, no. 9, pp. 1489–1500, 2003. View at Publisher · View at Google Scholar
  83. E. Burgermeister, A. Schnoebelen, A. Flament et al., “A novel partial agonist of peroxisome proliferator-activated receptor-? (PPAR?) recruits PPAR?-coactivator-1a, prevents triglyceride accumulation, and potentiates insulin signaling in vitro,” Molecular Endocrinology, vol. 20, no. 4, pp. 809–830, 2006. View at Publisher · View at Google Scholar
  84. S. A. Kliewer, B. M. Forman, B. Blumberg et al., “Differential expression and activation of a family of murine peroxisome proliferator-activated receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 15, pp. 7355–7359, 1994. View at Publisher · View at Google Scholar
  85. J. Padilla, E. Leung, and R. P. Phipps, “Human B lymphocytes and B lymphomas express PPAR-γ and are killed by PPAR-γ agonists,” Clinical Immunology, vol. 103, no. 1, pp. 22–33, 2002. View at Publisher · View at Google Scholar
  86. S. G. Harris and R. P. Phipps, “The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis,” European Journal of Immunology, vol. 31, no. 4, pp. 1098–1105, 2001. View at Publisher · View at Google Scholar
  87. F. Akbiyik, D. M. Ray, K. F. Gettings, N. Blumberg, C. W. Francis, and R. P. Phipps, “Human bone marrow megakaryocytes and platelets express PPARγ, and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes,” Blood, vol. 104, no. 5, pp. 1361–1368, 2004. View at Publisher · View at Google Scholar
  88. M. Ricote, J. Huang, L. Fajas et al., “Expression of the peroxisome proliferator-activated receptor ? (PPAR?) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 13, pp. 7614–7619, 1998. View at Publisher · View at Google Scholar
  89. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, pp. 79–82, 1998. View at Publisher · View at Google Scholar
  90. P. Gosset, A.-S. Charbonnier, P. Delerive et al., “Peroxisome proliferator-activated receptor ? activators affect the maturation of human monocyte-derived dendritic cells,” European Journal of Immunology, vol. 31, no. 10, pp. 2857–2865, 2001. View at Google Scholar
  91. R. B. Clark, “The role of PPARs in inflammation and immunity,” Journal of Leukocyte Biology, vol. 71, no. 3, pp. 388–400, 2002. View at Google Scholar
  92. R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula, “The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses,” Journal of Immunology, vol. 164, no. 3, pp. 1364–1371, 2000. View at Google Scholar
  93. D. M Ray, F. Akbiyik, S. H. Bernstein, and R. P. Phipps, “CD40 engagement prevents peroxisome proliferator-activated receptor γ agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-κB-dependent mechanism,” The Journal of Immunology, vol. 174, no. 7, pp. 4060–4069, 2005. View at Google Scholar
  94. D. M. Ray, F. Akbiyik, and R. P. Phipps, “The peroxisome proliferator-activated receptor γ (PPARγ) ligands 15-deoxy-Δ12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARγ-independent mechanisms,” The Journal of Immunology, vol. 177, no. 8, pp. 5068–76, 2006. View at Google Scholar
  95. A. Chawla, Y. Barak, L. Nagy, D. Liao, P. Tontonoz, and R. M. Evans, “PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation,” Nature Medicine, vol. 7, no. 1, pp. 48–52, 2001. View at Publisher · View at Google Scholar
  96. C.-H. Lee and R. M. Evans, “Peroxisome proliferator-activated receptor-γ in macrophage lipid homeostasis,” Trends in Endocrinology & Metabolism, vol. 13, no. 8, pp. 331–335, 2002. View at Publisher · View at Google Scholar
  97. P. Tontonoz, L. Nagy, J. G. A. Alvarez, V. A. Thomazy, and R. M. Evans, “PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL,” Cell, vol. 93, no. 2, pp. 241–252, 1998. View at Publisher · View at Google Scholar
  98. L. Nagy, P. Tontonoz, J. G. A. Alvarez, H. Chen, and R. M. Evans, “Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ,” Cell, vol. 93, no. 2, pp. 229–240, 1998. View at Publisher · View at Google Scholar
  99. C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998. View at Publisher · View at Google Scholar
  100. M. Ricote, J. S. Welch, and C. K. Glass, “Regulation of macrophage gene expression by the peroxisome proliferator-activated receptor-γ,” Hormone Research, vol. 54, no. 5-6, pp. 275–280, 2000. View at Publisher · View at Google Scholar
  101. M. A. Bouhlel, B. Derudas, E. Rigamonti et al., “PPAR? activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties,” Cell Metabolism, vol. 6, no. 2, pp. 137–143, 2007. View at Publisher · View at Google Scholar
  102. I. Szatmari, P. Gogolak, J. S. Im, B. Dezso, E. Rajnavolgyi, and L. Nagy, “Activation of PPARγ specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion,” Immunity, vol. 21, no. 1, pp. 95–106, 2004. View at Publisher · View at Google Scholar
  103. S. G. Harris and R. P. Phipps, “Prostaglandin D2, its metabolite 15-d-PGJ2, and peroxisome proliferator activated receptor-γ agonists induce apoptosis in transformed, but not normal, human T lineage cells,” Immunology, vol. 105, no. 1, pp. 23–34, 2002. View at Publisher · View at Google Scholar
  104. S. G. Harris and R. P. Phipps, “Induction of apoptosis in mouse T cells upon peroxisome proliferator-activated receptor gamma (PPAR-gamma) binding,” Advances in Experimental Medicine & Biology, vol. 507, pp. 421–425, 2002. View at Google Scholar
  105. H. J. Kim, Y. H. Rho, S. J. Choi et al., “15-deoxy-?12,14-PGJ2 inhibits IL-6-induced Stat3 phosphorylation in lymphocytes,” Experimental and Molecular Medicine, vol. 37, no. 3, pp. 179–185, 2005. View at Google Scholar
  106. M. Soller, A. Tautenhahn, B. Brüne et al., “Peroxisome proliferator-activated receptor ? contributes to T lymphocyte apoptosis during sepsis,” Journal of Leukocyte Biology, vol. 79, no. 1, pp. 235–243, 2006. View at Publisher · View at Google Scholar
  107. X. Y. Yang, L. H. Wang, T. Chen et al., “Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor ? (PPAR?) agonists. PPAR? co-association with transcription factor NFAT,” Journal of Biological Chemistry, vol. 275, no. 7, pp. 4541–4544, 2000. View at Publisher · View at Google Scholar
  108. E. A. Wohlfert, F. C. Nichols, E. Nevius, and R. B. Clark, “Peroxisome proliferator-activated receptor γ (PPARγ) and immunoregulation: enhancement of regulatory T cells through PPARγ-dependent and -independent mechanisms,” The Journal of Immunology, vol. 178, no. 7, pp. 4129–4135, 2007. View at Google Scholar
  109. S. Paust and H. Cantor, “Regulatory T cells and autoimmune disease,” Immunological Reviews, vol. 204, no. 1, pp. 195–207, 2005. View at Publisher · View at Google Scholar
  110. S. Onizuka, I. Tawara, J. Shimizu, S. Sakaguchi, T. Fujita, and E. Nakayama, “Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody,” Cancer Research, vol. 59, no. 13, pp. 3128–3133, 1999. View at Google Scholar
  111. M. Edinger, P. Hoffmann, J. Ermann et al., “CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation,” Nature Medicine, vol. 9, no. 9, pp. 1144–1150, 2003. View at Publisher · View at Google Scholar
  112. K. Setoguchi, Y. Misaki, Y. Terauchi et al., “Peroxisome proliferator-activated receptor-? haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis,” Journal of Clinical Investigation, vol. 108, no. 11, pp. 1667–1675, 2001. View at Publisher · View at Google Scholar
  113. J. Padilla, K. Kaur, H. J. Cao, T. J. Smith, and R. P. Phipps, “Peroxisome proliferator activator receptor-γ agonists and 15-deoxy-Δ12,14-PGJ2 induce apoptosis in normal and malignant B-lineage cells,” Journal of Immunology, vol. 165, no. 12, pp. 6941–6948, 2000. View at Google Scholar
  114. P. Desreumaux, L. Dubuquoy, S. Nutten et al., “Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor ? (PPAR?) heterodimer: a basis for new therapeutic strategies,” Journal of Experimental Medicine, vol. 193, no. 7, pp. 827–838, 2001. View at Publisher · View at Google Scholar
  115. C. G. Su, X. Wen, S. T. Bailey et al., “A novel therapy for colitis utilizing PPAR-? ligands to inhibit the epithelial inflammatory response,” Journal of Clinical Investigation, vol. 104, no. 4, pp. 383–389, 1999. View at Publisher · View at Google Scholar
  116. J. D. Lewis, G. R. Lichtenstein, R. B. Stein et al., “An open-label trial of the PPAR? ligand rosiglitazone for active ulcerative colitis,” The American Journal of Gastroenterology, vol. 96, no. 12, pp. 3323–3328, 2001. View at Publisher · View at Google Scholar
  117. K. Katayama, K. Wada, A. Nakajima et al., “A novel PPAR? gene therapy to control inflammation associated with inflammatory bowel disease in a murine model,” Gastroenterology, vol. 124, no. 5, pp. 1315–1324, 2003. View at Publisher · View at Google Scholar
  118. K. L. Schaefer, S. Denevich, C. Ma et al., “Intestinal antiinflammatory effects of thiazolidenedione peroxisome proliferator-activated receptor-? ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms,” Inflammatory Bowel Diseases, vol. 11, no. 3, pp. 244–252, 2005. View at Publisher · View at Google Scholar
  119. C. Lytle, T. J. Tod, K. T. Vo, J. W. Lee, R. D. Atkinson, and D. S. Straus, “The peroxisome proliferator-activated receptor γ ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency,” Inflammatory Bowel Diseases, vol. 11, no. 3, pp. 231–243, 2005. View at Publisher · View at Google Scholar
  120. C. Natarajan, G. Muthian, Y. Barak, R. M. Evans, and J. J. Bright, “Peroxisome proliferator-activated receptor-γ-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis,” Journal of Immunology, vol. 171, no. 11, pp. 5743–5750, 2003. View at Google Scholar
  121. D. L. Feinstein, E. Galea, V. Gavrilyuk et al., “Peroxisome proliferator-activated receptor-? agonists prevent experimental autoimmune encephalomyelitis,” Annals of Neurology, vol. 51, no. 6, pp. 694–702, 2002. View at Publisher · View at Google Scholar
  122. A. Diab, C. Deng, J. D. Smith et al., “Peroxisome proliferator-activated receptor-? agonist 15-deoxy-?12,14-prostaglandin J2 ameliorates experimental autoimmune encephalomyelitis,” The Journal of Immunology, vol. 168, no. 5, pp. 2508–2515, 2002. View at Google Scholar
  123. Y. Kawahito, M. Kondo, Y. Tsubouchi et al., “15-deoxy-?12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats,” Journal of Clinical Investigation, vol. 106, no. 2, pp. 189–197, 2000. View at Publisher · View at Google Scholar
  124. H. Robertshaw and P. S. Friedmann, “Pioglitazone: a promising therapy for psoriasis,” British Journal of Dermatology, vol. 152, no. 1, pp. 189–191, 2005. View at Publisher · View at Google Scholar
  125. C. N. Ellis, J. Varani, G. J. Fisher et al., “Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-? inhibit keratinocyte proliferation,” Archives of Dermatology, vol. 136, no. 5, pp. 609–616, 2000. View at Publisher · View at Google Scholar
  126. M. Mao-Qiang, A. J. Fowler, M. Schmuth et al., “Peroxisome-proliferator-activated receptor (PPAR)-? activation stimulates keratinocyte differentiation,” Journal of Investigative Dermatology, vol. 123, no. 2, pp. 305–312, 2004. View at Publisher · View at Google Scholar
  127. H. P. Koeffler, “Peroxisome proliferator-activated receptor γ and cancers,” Clinical Cancer Research, vol. 9, no. 1, pp. 1–9, 2003. View at Google Scholar
  128. E. Mueller, M. Smith, P. Sarraf et al., “Effects of ligand activation of peroxisome proliferator-activated receptor ? in human prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 20, pp. 10990–10995, 2000. View at Publisher · View at Google Scholar
  129. P. Sarraf, E. Mueller, W. M. Smith et al., “Loss-of-function mutations in PPAR? associated with human colon cancer,” Molecular Cell, vol. 3, no. 6, pp. 799–804, 1999. View at Publisher · View at Google Scholar
  130. R. A. Gupta, P. Sarraf, E. Mueller et al., “Peroxisome proliferator-activated receptor ?-mediated differentiation: a mutation in colon cancer cells reveals divergent and cell type-specific mechanisms,” Journal of Biological Chemistry, vol. 278, no. 25, pp. 22669–22677, 2003. View at Publisher · View at Google Scholar
  131. T. J. Giordano, A. Y. M. Au, R. Kuick et al., “Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation,” Clinical Cancer Research, vol. 12, no. 7, pp. 1983–1993, 2006. View at Publisher · View at Google Scholar
  132. B. Johansson, R. Billström, U. Kristoffersson et al., “Deletion of chromosome arm 3p in hematologic malignancies,” Leukemia, vol. 11, no. 8, pp. 1207–1213, 1997. View at Publisher · View at Google Scholar
  133. G. D. Demetri, C. D. M. Fletcher, E. Mueller et al., “Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-? ligand troglitazone in patients with liposarcoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3951–3956, 1999. View at Publisher · View at Google Scholar
  134. T. Kubota, K. Koshizuka, E. A. Williamson et al., “Ligand for peroxisome proliferator-activated receptor ? (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo,” Cancer Research, vol. 58, no. 15, pp. 3344–3352, 1998. View at Google Scholar
  135. P. Sarraf, E. Mueller, D. Jones et al., “Differentiation and reversal of malignant changes in colon cancer through PPAR?,” Nature Medicine, vol. 4, no. 9, pp. 1046–1052, 1998. View at Publisher · View at Google Scholar
  136. T. Ikezoe, C. W. Miller, S. Kawano et al., “Mutational analysis of the peroxisome proliferator-activated receptor ? gene in human malignancies,” Cancer Research, vol. 61, no. 13, pp. 5307–5310, 2001. View at Google Scholar
  137. S. Theocharis, H. Kanelli, E. Politi et al., “Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade,” Lung Cancer, vol. 36, no. 3, pp. 249–255, 2002. View at Publisher · View at Google Scholar
  138. J. H. Jansen, A. Mahfoudi, S. Rambaud, C. Lavau, W. Wahli, and A. Dejean, “Multimeric complexes of the PML-retinoic acid receptor α fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 16, pp. 7401–7405, 1995. View at Publisher · View at Google Scholar
  139. S. A. Hamadani, T. Zhang, C. Dorrell et al., “X-retinoic acid receptor alpha fusion genes in acute promyelocytic leukemia interfere with retinoid and peroxisome-proliferator signaling pathways,” Blood, vol. 98, no. 11, p. 88a, 2001. View at Google Scholar
  140. M. Konopleva and M. Andreeff, “Role of peroxisome proliferator-activated receptor-γ in hematologic malignancies,” Current Opinion in Hematology, vol. 9, no. 4, pp. 294–302, 2002. View at Publisher · View at Google Scholar
  141. American Cancer Society, “Cancer Facts & Figures,” Atlanta, Ga, USA, 2007.
  142. J. M. Rowe, “Innovative approaches in the treatment and support of patients with acute myelogenous leukemia,” The Oncologist, vol. 12, supplement 2, p. 1, 2007. View at Google Scholar
  143. D. G. Tenen, “Disruption of differentiation in human cancer: AML shows the way,” Nature Reviews Cancer, vol. 3, no. 2, pp. 89–101, 2003. View at Publisher · View at Google Scholar
  144. K.-H. Lee, M.-Y. Chang, J.-I. Ahn et al., “Differential gene expression in retinoic acid-induced differentiation of acute promyelocytic leukemia cells, NB4 and HL-60 cells,” Biochemical and Biophysical Research Communications, vol. 296, no. 5, pp. 1125–1133, 2002. View at Publisher · View at Google Scholar
  145. M. S. Tallman, J. W. Andersen, C. A. Schiffer et al., “All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol,” Blood, vol. 100, no. 13, pp. 4298–4302, 2002. View at Publisher · View at Google Scholar
  146. S. Fujimura, J. Suzumiya, K. Nakamura, and J. Ono, “Effects of troglitazone on the growth and differentiation of hematopoietic cell lines,” International Journal of Oncology, vol. 13, no. 6, pp. 1263–1267, 1998. View at Google Scholar
  147. N. Yamakawa-Karakida, K. Sugita, T. Inukai et al., “Ligand activation of peroxisome proliferator-activated receptor ? induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity,” Cell Death and Differentiation, vol. 9, no. 5, pp. 513–526, 2002. View at Publisher · View at Google Scholar
  148. J. J. Liu, R. W. Huang, D. J. Lin et al., “Expression of survivin and bax/bcl-2 in peroxisome proliferator activated receptor-? ligands induces apoptosis on human myeloid leukemia cells in vitro,” Annals of Oncology, vol. 16, no. 3, pp. 455–459, 2005. View at Publisher · View at Google Scholar
  149. J.-J. Liu, P.-Q. Liu, D.-J. Lin et al., “Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-? agonists induced apoptosis in human monocyte leukemia cells in vitro,” Annals of Hematology, vol. 86, no. 3, pp. 173–183, 2007. View at Publisher · View at Google Scholar
  150. H. Han, S.-W. Shin, C.-Y. Seo et al., “15-deoxy-?12,14-prostaglandin J2 (15d-PGJ2) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation,” Apoptosis, vol. 12, no. 11, pp. 2101–2114, 2007. View at Publisher · View at Google Scholar
  151. S. Nakata, T. Yoshida, T. Shiraishi et al., “15-deoxy-?12,14-prostaglandin J2 induces death receptor 5 expression through mRNA stabilization independently of PPAR? and potentiates TRAIL-induced apoptosis,” Molecular Cancer Therapeutics, vol. 5, no. 7, pp. 1827–1835, 2006. View at Publisher · View at Google Scholar
  152. A. Sugimura, Y. Kiriyama, H. Nochi et al., “Troglitazone suppresses cell growth of myeloid leukemia cell lines by induction of p21WAF1/CIP1 cyclin-dependent kinase inhibitor,” Biochemical and Biophysical Research Communications, vol. 261, no. 3, pp. 833–837, 1999. View at Publisher · View at Google Scholar
  153. J. Liu, H. Lu, R. Huang et al., “Peroxisome proliferator activated receptor-? ligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemia cells,” Cancer Chemotherapy and Pharmacology, vol. 56, no. 4, pp. 400–408, 2005. View at Publisher · View at Google Scholar
  154. R. Contractor, I. J. Samudio, Z. Estrov et al., “A novel ring-substituted diindolylmethane, 1,1-bis[3'-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane, inhibits extracellular signal-regulated kinase activation and induces apoptosis in acute myelogenous leukemia,” Cancer Research, vol. 65, no. 7, pp. 2890–2898, 2005. View at Publisher · View at Google Scholar
  155. M. Konopleva, E. Elstner, T. J. McQueen et al., “Peroxisome proliferator-activated receptor ? and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias,” Molecular Cancer Therapeutics, vol. 3, no. 10, pp. 1249–1262, 2004. View at Google Scholar
  156. N. Hirase, T. Yanase, Y.-M. Mu et al., “Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60,” Oncology, vol. 57, supplement 2, pp. 17–25, 1999. View at Publisher · View at Google Scholar
  157. H. Asou, W. Verbeek, E. Williamson et al., “Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor gamma, and retinoids,” International Journal of Oncology, vol. 15, no. 5, pp. 1027–1031, 1999. View at Google Scholar
  158. E. Yasugi, A. Horiuchi, I. Uemura et al., “Peroxisome proliferator-activated receptor ? ligands stimulate myeloid differentiation and lipogenensis in human leukemia NB4 cells,” Development Growth and Differentiation, vol. 48, no. 3, pp. 177–188, 2006. View at Publisher · View at Google Scholar
  159. M. Konopleva, T. Tsao, P. Ruvolo et al., “Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia,” Blood, vol. 99, no. 1, pp. 326–335, 2002. View at Publisher · View at Google Scholar
  160. Y. Ito, P. Pandey, A. Place et al., “The novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism,” Cell Growth and Differentiation, vol. 11, no. 5, pp. 261–267, 2000. View at Google Scholar
  161. N. Suh, Y. Wang, T. Honda et al., “A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity,” Cancer Research, vol. 59, no. 2, pp. 336–341, 1999. View at Google Scholar
  162. S. Koschmieder, F. D'Alò, H. Radomska et al., “CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer-binding protein alpha,” Blood, vol. 110, no. 10, pp. 3695–3705, 2007. View at Publisher · View at Google Scholar
  163. Y. Tabe, M. Konopleva, Y. Kondo et al., “PPAR?-active triterpenoid CDDO enhances ATRA-induced differentiation in APL,” Cancer Biology & Therapy, vol. 6, no. 12, pp. 1967–1977, 2007. View at Google Scholar
  164. M. Konopleva, T. Tsao, Z. Estrov et al., “The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia,” Cancer Research, vol. 64, no. 21, pp. 7927–7935, 2004. View at Publisher · View at Google Scholar
  165. T. A. Stadheim, N. Suh, N. Ganju, M. B. Sporn, and A. Eastman, “The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) potently enhances apoptosis induced by tumor necrosis factor in human leukemia cells,” Journal of Biological Chemistry, vol. 277, no. 19, pp. 16448–16455, 2002. View at Publisher · View at Google Scholar
  166. S. Shishodia, G. Sethi, M. Konopleva, M. Andreeff, and B. B. Aggarwal, “A synthetic triterpenoid, CDDO-Me, inhibits IκBα kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor κB-regulated gene products in human leukemic cells,” Clinical Cancer Research, vol. 12, pp. 1828–1838, 2006. View at Publisher · View at Google Scholar
  167. A. E. Place, N. Suh, C. R. Williams et al., “The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo,” Clinical Cancer Research, vol. 9, no. 7, pp. 2798–2806, 2003. View at Google Scholar
  168. T. Ikeda, M. Sporn, T. Honda, G. W. Gribble, and D. Kufe, “The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance,” Cancer Research, vol. 63, no. 17, pp. 5551–5558, 2003. View at Google Scholar
  169. S. Tsuchiya, M. Yamabe, Y. Yamaguchi, Y. Kobayashi, T. Konno, and K. Tada, “Establishment and characterization of a human acute monocytic leukemia cell line (THP-1),” International Journal of Cancer, vol. 26, no. 2, pp. 171–176, 1980. View at Publisher · View at Google Scholar
  170. L. Zhu, B. Gong, C. L. Bisgaier, M. Aviram, and R. S. Newton, “Induction of PPARγ1 expression in human THP-1 monocytic leukemia cells by 9-cis-retinoic acid is associated with cellular growth suppression,” Biochemical and Biophysical Research Communications, vol. 251, no. 3, pp. 842–848, 1998. View at Publisher · View at Google Scholar
  171. U. Kintscher, S. Goetze, S. Wakino et al., “Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes,” European Journal of Pharmacology, vol. 401, no. 3, pp. 259–270, 2000. View at Publisher · View at Google Scholar
  172. X. Xin, S. Yang, J. Kowalski, and M. E. Gerritsen, “Peroxisome proliferator-activated receptor γ ligands are potent inhibitors of angiogenesis in vitro and in vivo,” Journal of Biological Chemistry, vol. 274, no. 13, pp. 9116–9121, 1999. View at Publisher · View at Google Scholar
  173. T.-C. Ho, Y.-C. Yang, S.-L. Chen et al., “Pigment epithelium-derived factor induces THP-1 macrophage apoptosis and necrosis by the induction of the peroxisome proliferator-activated receptor ?,” Molecular Immunology, vol. 45, no. 4, pp. 898–909, 2008. View at Publisher · View at Google Scholar
  174. J. Sessions, “Chronic myeloid leukemia in 2007,” American Journal of Health-System Pharmacy, vol. 64, supplement 15, no. 24, pp. S4–S9, 2007. View at Publisher · View at Google Scholar
  175. A. Hochhaus, “Advances in the treatment of haematological malignancies: optimal sequence of CML treatment,” Annals of Oncology, vol. 18, supplement 9, pp. ix58–ix63, 2007. View at Publisher · View at Google Scholar
  176. A. Ikeda, D. B. Shankar, M. Watanabe, F. Tamanoi, T. B. Moore, and K. M. Sakamoto, “Molecular targets and the treatment of myeloid leukemia,” Molecular Genetics and Metabolism, vol. 88, no. 3, pp. 216–224, 2006. View at Publisher · View at Google Scholar
  177. N. P. Shah, J. M. Nicoll, B. Nagar et al., “Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia,” Cancer Cell, vol. 2, no. 2, pp. 117–125, 2002. View at Publisher · View at Google Scholar
  178. C. B. Lozzio and B. B. Lozzio, “Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome,” Blood, vol. 45, no. 3, pp. 321–334, 1975. View at Google Scholar
  179. H. Liu, C. Zang, M. H. Fenner et al., “Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARa/? ligand TZD18,” Blood, vol. 107, no. 9, pp. 3683–3692, 2006. View at Publisher · View at Google Scholar
  180. N. Hirase, T. Yanase, Y. Mu et al., “Thiazolidinedione suppresses the expression of erythroid phenotype in erythroleukemia cell line K562,” Leukemia Research, vol. 24, no. 5, pp. 393–400, 2000. View at Publisher · View at Google Scholar
  181. D. Hoelzer and N. Gökbuget, “Recent approaches in acute lymphoblastic leukemia in adults,” Critical Reviews in Oncology/Hematology, vol. 36, no. 1, pp. 49–58, 2000. View at Publisher · View at Google Scholar
  182. C.-H. Pui and S. Jeha, “New therapeutic strategies for the treatment of acute lymphoblastic leukaemia,” Nature Reviews Drug Discovery, vol. 6, no. 2, pp. 149–165, 2007. View at Publisher · View at Google Scholar
  183. A. Stamatoullas, G. Buchonnet, S. Lepretre et al., “De novo acute B cell leukemia/lymphoma with t(14;18),” Leukemia, vol. 14, no. 11, pp. 1960–1966, 2000. View at Publisher · View at Google Scholar
  184. C. Patte, “Treatment of mature B-ALL and high grade B-NHL in children,” Best Practice & Research in Clinical Haematology, vol. 15, no. 4, pp. 695–711, 2002. View at Publisher · View at Google Scholar
  185. N. C. Popescu and D. B. Zimonjic, “Chromosome-mediated alterations of the MYC gene in human cancer,” Journal of Cellular and Molecular Medicine, vol. 6, no. 2, pp. 151–159, 2002. View at Publisher · View at Google Scholar
  186. C. Zang, H. Liu, M. G. Posch et al., “Peroxisome proliferator-activated receptor ? ligands induce growth inhibition and apoptosis of human B lymphocytic leukemia,” Leukemia Research, vol. 28, no. 4, pp. 387–397, 2004. View at Publisher · View at Google Scholar
  187. M. Takenokuchi, K. Saigo, Y. Nakamachi et al., “Troglitazone inhibits cell growth and induces apoptosis of B-cell acute lymphoblastic leukemia cells with t(14;18),” Acta Haematologica, vol. 116, no. 1, pp. 30–40, 2006. View at Publisher · View at Google Scholar
  188. T. Tsubata, J. Wu, and T. Honjo, “B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40,” Nature, vol. 364, no. 6438, pp. 645–648, 1993. View at Publisher · View at Google Scholar
  189. R. Piva, P. Gianferretti, A. Ciucci, R. Taulli, G. Belardo, and M. G. Santoro, “15-deoxy-Δ12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-κB activity and down-regulation of antiapoptotic proteins,” Blood, vol. 105, no. 4, pp. 1750–1758, 2005. View at Publisher · View at Google Scholar
  190. C. Yang, S.-H. Jo, B. Csernus et al., “Activation of peroxisome proliferator-activated receptor ? contributes to the survival of T lymphoma cells by affecting cellular metabolism,” American Journal of Pathology, vol. 170, no. 2, pp. 722–732, 2007. View at Publisher · View at Google Scholar
  191. M. Duvic, K. Hymes, P. Heald et al., “Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results,” Journal of Clinical Oncology, vol. 19, no. 9, pp. 2456–2471, 2001. View at Google Scholar
  192. C. Zhang, X. Ni, M. Konopleva, M. Andreeff, and M. Duvic, “The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in mycocis fungoides/Sézary syndrome cells,” Journal of Investigative Dermatology, vol. 123, no. 2, pp. 380–387, 2004. View at Publisher · View at Google Scholar
  193. O. A. O'Connor, “Mantle cell lymphoma: identifying novel molecular targets in growth and survival pathways,” Hematology, vol. 2007, pp. 270–276, 2007. View at Google Scholar
  194. R. I. Fisher, S. Dahlberg, B. N. Nathwani, P. M. Banks, T. P. Miller, and T. M. Grogan, “A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study,” Blood, vol. 85, no. 4, pp. 1075–1082, 1995. View at Google Scholar
  195. J. Eucker, J. Sterz, H. Krebbel et al., “Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma,” Anti-Cancer Drugs, vol. 17, no. 7, pp. 763–769, 2006. View at Publisher · View at Google Scholar
  196. N. Chiorazzi, K. R. Rai, and M. Ferrarini, “Chronic lymphocytic leukemia,” New England Journal of Medicine, vol. 352, no. 8, pp. 804–815–850, 2005. View at Publisher · View at Google Scholar
  197. D. A. Carney and W. G. Wierda, “Genetics and molecular biology of chronic lymphocytic leukemia,” Current Treatment Options in Oncology, vol. 6, no. 3, pp. 215–225, 2005. View at Publisher · View at Google Scholar
  198. M. Hanada, D. Delia, A. Aiello, E. Stadtmauer, and J. C. Reed, “bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia,” Blood, vol. 82, no. 6, pp. 1820–1828, 1993. View at Google Scholar
  199. I. M. Pedersen, S. Kitada, A. Schimmer et al., “The triterpenoid CDDO induces apoptosis in refractory CLL B cells,” Blood, vol. 100, no. 8, pp. 2965–2972, 2002. View at Publisher · View at Google Scholar
  200. S. Inoue, R. T. Snowden, M. J. S. Dyer, and G. M. Cohen, “CDDO induces apoptosis via the intrinsic pathway in lymphoid cells,” Leukemia, vol. 18, no. 5, pp. 948–952, 2004. View at Publisher · View at Google Scholar
  201. The Non-Hodgkin's Lymphoma Classification Project, “A clinical evaluation of the international lymphoma study group classification of non-Hodgkin's lymphoma,” Blood, vol. 89, no. 11, pp. 3909–3918, 1997. View at Google Scholar
  202. A. A. Alizadeh, M. B. Elsen, R. E. Davis et al., “Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling,” Nature, vol. 403, no. 6769, pp. 503–511, 2000. View at Publisher · View at Google Scholar
  203. R. D. Gascoyne, S. A. Adomat, S. Krajewski et al., “Prognostic significance of bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma,” Blood, vol. 90, no. 1, pp. 244–251, 1997. View at Google Scholar
  204. R. D. Gascoyne, “Emerging prognostic factors in diffuse large B cell lymphoma,” Current Opinion in Oncology, vol. 16, no. 5, pp. 436–441, 2004. View at Publisher · View at Google Scholar
  205. D. M. Ray, K. M. Morse, S. P. Hilchey et al., “The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor ?-independent pathway,” Experimental Hematology, vol. 34, no. 9, pp. 1202–1211, 2006. View at Publisher · View at Google Scholar
  206. P. S. Brookes, K. Morse, D. M. Ray et al., “The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore,” Cancer Research, vol. 67, no. 4, pp. 1793–1802, 2007. View at Publisher · View at Google Scholar
  207. S. V. Rajkumar and R. A. Kyle, “Multiple myeloma: diagnosis and treatment,” Mayo Clinic Proceedings, vol. 80, no. 10, pp. 1371–1382, 2005. View at Google Scholar
  208. M. A. Hussein, J. V. Juturi, and I. Lieberman, “Multiple myeloma: present and future,” Current Opinion in Oncology, vol. 14, no. 1, pp. 31–35, 2002. View at Publisher · View at Google Scholar
  209. P. J. Hayden, C. S. Mitsiades, K. C. Anderson, and P. G. Richardson, “Novel therapies in myeloma,” Current Opinion in Hematology, vol. 14, no. 6, pp. 609–615, 2007. View at Publisher · View at Google Scholar
  210. D. M. Ray, S. H. Bernstein, and R. P. Phipps, “Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands,” Clinical Immunology, vol. 113, no. 2, pp. 203–213, 2004. View at Publisher · View at Google Scholar
  211. J. Eucker, K. Bängeroth, I. Zavrski et al., “Ligands of peroxisome proliferator-activated receptor ? induce apoptosis in multiple myeloma,” Anti-Cancer Drugs, vol. 15, no. 10, pp. 955–960, 2004. View at Publisher · View at Google Scholar
  212. C. S. Mitsiades, N. Mitsiades, P. G. Richardson, S. P. Treon, and K. C. Anderson, “Novel biologically based therapies for Waldenstrom's macroglobulinemia,” Seminars in Oncology, vol. 30, no. 2, pp. 309–312, 2003. View at Publisher · View at Google Scholar
  213. L. H. Wang, X. Y. Yang, X. Zhang, and W. L. Farrar, “Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARγ cross talk with NF-κB and C/EBPβ,” Blood, vol. 110, no. 13, pp. 4373–4384, 2007. View at Publisher · View at Google Scholar
  214. T. Ikeda, Y. Nakata, F. Kimura et al., “Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3, 12-dioxoolean-1,9-dien-28-oic acid,” Molecular Cancer Therapeutics, vol. 3, no. 1, pp. 39–45, 2004. View at Google Scholar
  215. D. Chauhan, G. Li, K. Podar et al., “The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance,” Blood, vol. 103, no. 8, pp. 3158–3166, 2004. View at Publisher · View at Google Scholar
  216. K. Liby, N. Voong, C. R. Williams et al., “The synthetic triterpenoid CDDO-Imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells,” Clinical Cancer Research, vol. 12, no. 14, part 1, pp. 4288–4293, 2006. View at Google Scholar