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Antimyeloma activity of the sesquiterpene lactone cnicin: impact on Pim-2 kinase as a novel therapeutic target

Journal of Molecular Medicine volume 90, pages 681–693 (2012)Cite this article

Abstract

Despite recent advances in therapy, multiple myeloma, the second most common hematologic tumor in the Western world, is still incurable. Identification of substances that display a wide range of tumor-killing activities and target cancer-specific pathways constitute a basis for the development of novel therapies. In this study, we investigate the cytotoxic effect of the natural substance cnicin in multiple myeloma. Cnicin treatment reveals potent antiproliferative effects and induces cell death in cell lines and primary myeloma cells even in the presence of survival cytokines and the tumor microenvironment. Other cell lines of hematopoietic origin also succumb to cell death whereas stromal cells and endothelial cells are unaffected. We show that activation of caspases, accumulation of reactive oxygen species and downregulation of nuclear factor kappa-light-chain-enhancer of activated B cell contribute to the cytotoxic effects of cnicin. Microarray analysis reveals downregulation of Pim-2, a serine/threonine kinase. We provide evidence that Pim-2 constitutes a new survival kinase for myeloma cells in vitro and is highly expressed in malignant but not in normal plasma cells in vivo. Combining cnicin with current standard or experimental therapeutics leads to enhanced cell death. Thus, our data indicate that cnicin induces myeloma cell death via several pathways and reveals Pim-2 as a novel target. These findings provide a rational for further evaluation of cnicin as a new anti-tumor drug and underline the potential of sesquiterpene lactones in tumor therapy.

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References

  1. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V et al (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277:16639–16647

    Article  PubMed  CAS  Google Scholar 

  2. Kawauchi K, Ogasawara T, Yasuyama M, Otsuka K, Yamada O (2009) The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem 9:550–559

    PubMed  CAS  Google Scholar 

  3. Hideshima T, Akiyama M, Hayashi T, Richardson P, Schlossman R, Chauhan D, Anderson KC (2003) Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood 101:703–705

    Article  PubMed  CAS  Google Scholar 

  4. Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477

    Article  PubMed  CAS  Google Scholar 

  5. Bruno M, Rosselli S, Maggio A, Raccuglia RA, Bastow KF, Wu CC, Lee KH (2005) Cytotoxic activity of some natural and synthetic sesquiterpene lactones. Planta Med 71:1176–1178

    Article  PubMed  CAS  Google Scholar 

  6. Hung JY, Hsu YL, Ni WC, Tsai YM, Yang CJ, Kuo PL, Huang MS (2010) Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells. Lung Cancer 68:355–365

    Article  PubMed  Google Scholar 

  7. Ichikawa H, Nair MS, Takada Y, Sheeja DB, Kumar MA, Oommen OV, Aggarwal BB (2006) Isodeoxyelephantopin, a novel sesquiterpene lactone, potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis through suppression of nuclear factor-kappaB (nf-kappaB) activation and nf-kappaB-regulated gene expression. Clin Cancer Res 12:5910–5918

    Article  PubMed  CAS  Google Scholar 

  8. Lee J, Hwangbo C, Lee JJ, Seo J, Lee JH (2010) The sesquiterpene lactone eupatolide sensitizes breast cancer cells to TRAIL through down-regulation of c-FLIP expression. Oncol Rep 23:229–237

    PubMed  CAS  Google Scholar 

  9. Lesiak K, Koprowska K, Zalesna I, Nejc D, Duchler M, Czyz M (2010) Parthenolide, a sesquiterpene lactone from the medical herb feverfew, shows anticancer activity against human melanoma cells in vitro. Melanoma Res 20:21–34

    Article  PubMed  CAS  Google Scholar 

  10. Saroglou V, Karioti A, Demetzos C, Dimas K, Skaltsa H (2005) Sesquiterpene lactones from Centaurea spinosa and their antibacterial and cytotoxic activities. J Nat Prod 68:1404–1407

    Article  PubMed  CAS  Google Scholar 

  11. Steele AJ, Jones DT, Ganeshaguru K, Duke VM, Yogashangary BC, North JM, Lowdell MW, Kottaridis PD, Mehta AB, Prentice AG et al (2006) The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 20:1073–1079

    Article  PubMed  CAS  Google Scholar 

  12. Suvannasankha A, Crean CD, Shanmugam R, Farag SS, Abonour R, Boswell HS, Nakshatri H (2008) Antimyeloma effects of a sesquiterpene lactone parthenolide. Clin Cancer Res 14:1814–1822

    Article  PubMed  CAS  Google Scholar 

  13. Wang W, Adachi M, Kawamura R, Sakamoto H, Hayashi T, Ishida T, Imai K, Shinomura Y (2006) Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity. Apoptosis 11:2225–2235

    Article  PubMed  CAS  Google Scholar 

  14. Vanhaelen-Fastre R, Vanhaelen M (1976) Antibiotic and cytotoxic activity of cnicin and of its hydrolysis products. Chemical structure–biological activity relationship. Planta Med 29:179–189 (author’s transl)

    Article  PubMed  CAS  Google Scholar 

  15. Schneider G, Lachner I (1987) Analysis and action of cnicin. Planta Med 53:247–251

    Article  PubMed  CAS  Google Scholar 

  16. Woodland RT, Fox CJ, Schmidt MR, Hammerman PS, Opferman JT, Korsmeyer SJ, Hilbert DM, Thompson CB (2008) Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival. Blood 111:750–760

    Article  PubMed  CAS  Google Scholar 

  17. Cohen AM, Grinblat B, Bessler H, Kristt D, Kremer A, Schwartz A, Halperin M, Shalom S, Merkel D, Don J (2004) Increased expression of the hPim-2 gene in human chronic lymphocytic leukemia and non-Hodgkin lymphoma. Leuk Lymphoma 45:951–955

    Article  PubMed  CAS  Google Scholar 

  18. Claudio JO, Masih-Khan E, Tang H, Goncalves J, Voralia M, Li ZH, Nadeem V, Cukerman E, Francisco-Pabalan O, Liew CC et al (2002) A molecular compendium of genes expressed in multiple myeloma. Blood 100:2175–2186

    Article  PubMed  CAS  Google Scholar 

  19. Asano J, Nakano A, Oda A, Amou H, Hiasa M, Takeuchi K, Miki H, Nakamura S, Harada T, Fujii S et al (2011) The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells. Leukemia 25:1182–1188

    Article  PubMed  CAS  Google Scholar 

  20. Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB (2003) The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev 17:1841–1854

    Article  PubMed  CAS  Google Scholar 

  21. Amson R, Sigaux F, Przedborski S, Flandrin G, Givol D, Telerman A (1989) The human protooncogene product p33pim is expressed during fetal hematopoiesis and in diverse leukemias. Proc Natl Acad Sci U S A 86:8857–8861

    Article  PubMed  CAS  Google Scholar 

  22. Fox CJ, Hammerman PS, Thompson CB (2005) The Pim kinases control rapamycin-resistant T cell survival and activation. J Exp Med 201:259–266

    Article  PubMed  CAS  Google Scholar 

  23. Hammerman PS, Fox CJ, Birnbaum MJ, Thompson CB (2005) Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood 105:4477–4483

    Article  PubMed  CAS  Google Scholar 

  24. Chen JL, Limnander A, Rothman PB (2008) Pim-1 and Pim-2 kinases are required for efficient pre-B-cell transformation by v-Abl oncogene. Blood 111:1677–1685

    Article  PubMed  CAS  Google Scholar 

  25. Allen JD, Verhoeven E, Domen J, van der Valk M, Berns A (1997) Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc. Oncogene 15:1133–1141

    Article  PubMed  CAS  Google Scholar 

  26. Zhang Y, Wang Z, Li X, Magnuson NS (2008) Pim kinase-dependent inhibition of c-Myc degradation. Oncogene 27:4809–4819

    Article  PubMed  CAS  Google Scholar 

  27. Breuer ML, Cuypers HT, Berns A (1989) Evidence for the involvement of pim-2, a new common proviral insertion site, in progression of lymphomas. EMBO J 8:743–748

    PubMed  CAS  Google Scholar 

  28. Schatz JH, Oricchio E, Wolfe AL, Jiang M, Linkov I, Maragulia J, Shi W, Zhang Z, Rajasekhar VK, Pagano NC et al (2011) J Exp Med 208:1799–1807

    Article  PubMed  CAS  Google Scholar 

  29. Greenstein S, Krett NL, Kurosawa Y, Ma C, Chauhan D, Hideshima T, Anderson KC, Rosen ST (2003) Characterization of the MM.1 human multiple myeloma (MM) cell lines: a model system to elucidate the characteristics, behavior, and signaling of steroid-sensitive and -resistant MM cells. Exp Hematol 31:271–282

    Article  PubMed  CAS  Google Scholar 

  30. Rood PM, Calafat J, von dem Borne AE, Gerritsen WR, van der Schoot CE (2000) Immortalisation of human bone marrow endothelial cells: characterisation of new cell lines. Eur J Clin Invest 30:618–629

    Article  PubMed  CAS  Google Scholar 

  31. Deryugina EI, Quigley JP (2008) Chapter 2. Chick embryo chorioallantoic membrane models to quantify angiogenesis induced by inflammatory and tumor cells or purified effector molecules. Methods Enzymol 444:21–41

    Article  PubMed  CAS  Google Scholar 

  32. Kulterer B, Friedl G, Jandrositz A, Sanchez-Cabo F, Prokesch A, Paar C, Scheideler M, Windhager R, Preisegger KH, Trajanoski Z (2007) Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation. BMC Genomics 8:70–76

    Article  PubMed  Google Scholar 

  33. Choi EJ, Ahn WS (2009) Antiproliferative effects of dehydrocostuslactone through cell cycle arrest and apoptosis in human ovarian cancer SK-OV-3 cells. Int J Mol Med 23:211–216

    Article  PubMed  CAS  Google Scholar 

  34. Kunzi-Rapp K, Genze F, Kufer R, Reich E, Hautmann RE, Gschwend JE (2001) Chorioallantoic membrane assay: vascularized 3-dimensional cell culture system for human prostate cancer cells as an animal substitute model. J Urol 166:1502–1507

    Article  PubMed  CAS  Google Scholar 

  35. Saw CL, Heng PW, Liew CV (2008) Chick chorioallantoic membrane as an in situ biological membrane for pharmaceutical formulation development: a review. Drug Dev Ind Pharm 34:1168–1177

    Article  PubMed  CAS  Google Scholar 

  36. Taizi M, Deutsch VR, Leitner A, Ohana A, Goldstein RS (2006) A novel and rapid in vivo system for testing therapeutics on human leukemias. Exp Hematol 34:1698–1708

    Article  PubMed  CAS  Google Scholar 

  37. Parada-Turska J, Paduch R, Majdan M, Kandefer.Szerszen M, Rzeski W (2007) Antiproliferative activity of parthenolide against three human cancer cell lines and umbilical vein endothelial cells. Pharmacol Rep 59:233–237

    PubMed  CAS  Google Scholar 

  38. Zunino SJ, Storms DH, Ducore JM (2010) Parthenolide treatment activates stress signaling proteins in high-risk acute lymphoblastic leukemia cells with chromosomal translocation t(4;11). Int J Oncol 37:1307–1313

    Article  PubMed  CAS  Google Scholar 

  39. Clerkin JS, Naughton R, Quiney C, Cotter TG (2008) Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett 266:30–36

    Article  PubMed  CAS  Google Scholar 

  40. Amaravadi R, Thompson CB (2005) The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 115:2618–2624

    Article  PubMed  CAS  Google Scholar 

  41. Zollinger A, Stuhmer T, Chatterjee M, Gattenlohner S, Haralambieva E, Muller-Hermelink HK, Andrulis M, Greiner A, Wesemeier C, Rath JC et al (2008) Combined functional and molecular analysis of tumor cell signaling defines 2 distinct myeloma subgroups: Akt-dependent and Akt-independent multiple myeloma. Blood 112:3403–3411

    Article  PubMed  Google Scholar 

  42. Dai H, Li R, Wheeler T, Diaz DV, Frolov A, Tahir S, Agoulnik I, Thompson T, Rowley D, Ayala G (2005) Pim-2 upregulation: biological implications associated with disease progression and perinueral invasion in prostate cancer. Prostate 65:276–286

    Article  PubMed  CAS  Google Scholar 

  43. Behan JW, Yun JP, Proektor MP, Ehsanipour EA, Arutyunyan A, Moses AS, Avramis VI, Louie SG, Butturini A, Heisterkamp N et al (2009) Adipocytes impair leukemia treatment in mice. Cancer Res 69:7867–7874

    Article  PubMed  CAS  Google Scholar 

  44. Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA, Darwiche N (2010) What made sesquiterpene lactones reach clinical trials? Drug Discov Today 15:668–678

    Article  PubMed  CAS  Google Scholar 

  45. Merfort I (2011) Perspectives on sesquiterpene actones in inflammation and cancer. Curr Drug Targets 12:1560–1573

    Article  PubMed  CAS  Google Scholar 

  46. Curry EA 3rd, Murry DJ, Yoder C, Fife K, Armstrong V, Nakshatri H, O’Connell M, Sweeney CJ (2004) Invest New Drugs 22:299–305

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Katrin Janke and Claudia Zavadil for their excellent technical assistance. This project was supported by grants of the Austrian Cancer Society/Tirol (to KJ, MO, and JP), the SFB021 (to RG), and the Klinische Malignom- und Zytokinforschung Innsbruck-Salzburg gemeinnützige GmbH.

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Authors and Affiliations

  1. Tyrolean Cancer Research Institute, Innrain 66, 6020, Innsbruck, Austria

    Karin Jöhrer, Marlene Obkircher, Johanna Parteli, Claudia Zelle-Rieser, Eva Maizner & Richard Greil

  2. Institute of Pathology, University Hospital Salzburg, Müllner Hauptstrasse 48, 5020, Salzburg, Austria

    Daniel Neureiter

  3. Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria

    Johann Kern

  4. KMT Laboratory, Department of Visceral-, Transplant- and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria

    Martin Hermann

  5. Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, University Hospital Salzburg, Salzburg, Austria

    Frank Hamacher, Olaf Merkel, Nathalie Wacht & Richard Greil

  6. Institute of Pharmacy, Department of Pharmacognosy, University of Innsbruck, Innsbruck, Austria

    Christian Zidorn

  7. Institute for Genomics and Bioinformatics, Graz University of Technology, Petersgasse 14, 8010, Graz, Austria

    Marcel Scheideler

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  1. Karin Jöhrer
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Correspondence to Karin Jöhrer.

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Jöhrer, K., Obkircher, M., Neureiter, D. et al. Antimyeloma activity of the sesquiterpene lactone cnicin: impact on Pim-2 kinase as a novel therapeutic target. J Mol Med 90, 681–693 (2012). https://doi.org/10.1007/s00109-011-0848-x

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