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.

  • Spotlight
  • Published:

Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis

Leukemia volume 19, pages 901–909 (2005)Cite this article

Abstract

In multiple myeloma (MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM. We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells (HUVECs). Five myeloma cell lines produced varying amounts of VEGF, and migration of HUVECs was induced by coculture with myeloma cells. We next examined the inhibitory effect of a novel synthetic retinoid Am80 (Tamibarotene) on both myeloma cells and HUVECs. Am80 is specific for the retinoic-acid receptor-α/β, and has therapeutic effects in all-trans retinoic acid resistant acute promyelocytic leukemia. Am80 slightly inhibited the growth of both myeloma cells and HUVECs, and remarkably inhibited the growth of HUVECs stimulated by VEGF. Am80 showed little growth inhibition of bone marrow stromal cells (BMSCs), but it markedly inhibited migration of HUVECs by cocultured myeloma cells. Am80 inhibited VEGF-induced phosphorylation of VEGF receptor. In addition, VEGF-induced formation of tube-like structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80. These findings clearly demonstrate that Am80 is a potential inhibitor of angiogenesis caused by the interaction between vascular endothelial cells and myeloma cells, and might be a useful therapeutic agent against MM.

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
Figure 8

References

  1. Iida S, Ueda R . Multistep tumorigenesis of multiple myeloma: its molecular delineation. Int J Hematol 2003; 77: 207–212.

    Article  CAS  PubMed  Google Scholar 

  2. Hideshima T, Anderson KC . Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002; 2: 927–937.

    Article  CAS  PubMed  Google Scholar 

  3. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromall cell interactions in multiple myeloma. Blood 2000; 95: 2630–2636.

    CAS  PubMed  Google Scholar 

  4. Urashima M, Ogata A, Chauhan D, Vidriales MB, Teoh G, Hoshi Y et al. Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood 1996; 88: 2219–2227.

    CAS  PubMed  Google Scholar 

  5. Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994; 87: 503–508.

    Article  CAS  PubMed  Google Scholar 

  6. Ribatti D, Vacca A, Nico B, Quondamatteo F, Ria R, Minischetti M et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer 1999; 79: 451–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Giuliani N, Colla S, Lazzaretti M, Sala R, Roti G, Mancini C et al. Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis. Blood 2003; 102: 638–645.

    Article  CAS  PubMed  Google Scholar 

  8. Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997; 57: 4593–4599.

    CAS  PubMed  Google Scholar 

  9. Bellamy WT, Richter L, Sirjani D, Roxas C, Glinsmann-Gibson B, Frutiger Y et al. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood 2001; 97: 1427–1434.

    Article  CAS  PubMed  Google Scholar 

  10. Lin B, Podar K, Gupta D, Tai YT, Li S, Weller E et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res 2002; 62: 5019–5026.

    CAS  PubMed  Google Scholar 

  11. Moehler TM, Ho AD, Goldschmidt H, Barlogie B . Angiogenesis in hematologic malignancies. Crit Rev Oncol Hematol 2003; 45: 227–244.

    Article  CAS  PubMed  Google Scholar 

  12. D'Amato RJ, Loughnan MS, Flynn E, Folkman J . Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91: 4082–4085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Breitman TR, Selonick SE, Collins SJ . Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci USA 1980; 77: 2936–2940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ponzoni M, Bocca P, Chiesa V, Decensi A, Pistoia V, Raffaghello L et al. Differential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis vs differentiation. Cancer Res 1995; 55: 853–861.

    CAS  PubMed  Google Scholar 

  15. Lu XP, Fanjul A, Picard N, Pfahl M, Rungta D, Nared-Hood K et al. Novel retinoid-related molecules as apoptosis inducers and effective inhibitors of human lung cancer cells in vivo. Nat Med 1997; 3: 686–690.

    Article  CAS  PubMed  Google Scholar 

  16. Chen YH, Desai P, Shiao RT, Lavelle D, Haleem A, Chen J . Inhibition of myeloma cell growth by dexamethasone and all-trans retinoic acid: synergy through modulation of interleukin-6 autocrine loop at multiple sites. Blood 1996; 87: 314–323.

    CAS  PubMed  Google Scholar 

  17. Taetle R, Dos Santos B, Akamatsu K, Koishihara Y, Ohsugi Y . Effects of all-trans retinoic acid and antireceptor antibodies on growth and programmed cell death of human myeloma cells. Clin Cancer Res 1996; 2: 253–259.

    CAS  PubMed  Google Scholar 

  18. Ogata A, Nishimoto N, Shima Y, Yoshizaki K, Kishimoto T . Inhibitory effect of all-trans retinoic acid on the growth of freshly isolated myeloma cells via interference with interleukin-6 signal transduction. Blood 1994; 84: 3040–3046.

    CAS  PubMed  Google Scholar 

  19. Delva L, Cornic M, Balitrand N, Guidez F, Miclea JM, Delmer A et al. Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood 1993; 82: 2175–2181.

    CAS  PubMed  Google Scholar 

  20. Takagi K, Suganuma M, Kagechika H, Shudo K, Ninomiya M, Muto Y et al. Inhibition of ornithine decarboxylase induction by retinobenzoic acids in relation to their binding affinities to cellular retinoid-binding proteins. J Cancer Res Clin Oncol 1988; 114: 221–224.

    Article  CAS  PubMed  Google Scholar 

  21. Hashimoto Y, Kagechika H, Shudo K . Expression of retinoic acid receptor genes and the ligand-binding selectivity of retinoic acid receptors (RAR's). Biochem Biophys Res Commun 1990; 166: 1300–1307.

    Article  CAS  PubMed  Google Scholar 

  22. Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiraoka A et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood 1997; 90: 967–973.

    CAS  PubMed  Google Scholar 

  23. Kagechika H, Kawachi E, Fukasawa H, Saito G, Iwanami N, Umemiya H et al. Inhibition of IL-1-induced IL-6 production by synthetic retinoids. Biochem Biophys Res Commun 1997; 231: 243–248.

    Article  CAS  PubMed  Google Scholar 

  24. Oikawa T, Okayasu I, Ashino H, Morita I, Murota S, Shudo K . Three novel synthetic retinoids, Re 80, Am 580 and Am 80, all exhibit anti-angiogenic activity in vivo. Eur J Pharmacol 1993; 249: 113–116.

    Article  CAS  PubMed  Google Scholar 

  25. Sanda T, Iida S, Ogura H, Asamitsu K, Murata T, Bacon KB et al. Growth inhibition of multiple myeloma cells by a novel IkB kinase inhibitor. Clin Cancer Res 2005; 11: 1974–1982.

    Article  CAS  PubMed  Google Scholar 

  26. Hayami Y, Iida S, Nakazawa N, Hanamura I, Kato M, Komatsu H et al. Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in human multiple myeloma. Leukemia 2003; 17: 1650–1657.

    Article  CAS  PubMed  Google Scholar 

  27. Kagechika H, Kawachi E, Hashimoto Y, Himi T, Shudo K . Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity. J Med Chem 1988; 31: 2182–2192.

    Article  CAS  PubMed  Google Scholar 

  28. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999; 59: 99–106.

    CAS  PubMed  Google Scholar 

  29. Kuwano T, Nakao S, Yamamoto H, Tsuneyoshi M, Yamamoto T, Kuwano M et al. Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. FASEB J 2004; 18: 300–310.

    Article  CAS  PubMed  Google Scholar 

  30. Itokawa T, Nokihara H, Nishioka Y, Sone S, Iwamoto Y, Yamada Y et al. Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. Mol Cancer Ther 2002; 1: 295–302.

    CAS  PubMed  Google Scholar 

  31. Hirata A, Ogawa S, Kometani T, Kuwano T, Naito S, Kuwano M et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002; 62: 2554–2560.

    CAS  PubMed  Google Scholar 

  32. Nefedova Y, Landowski TH, Dalton WS . Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia 2003; 17: 1175–1182.

    Article  CAS  PubMed  Google Scholar 

  33. Koskela K, Pelliniemi TT, Pulkki K, Remes K . Treatment of multiple myeloma with all-trans retinoic acid alone and in combination with chemotherapy: a phase I/II trial. Leuk Lymphoma 2004; 45: 749–754.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr H Kagechika (University of Tokyo, Tokyo, Japan) for the kind gift of Am80. This work is supported in part by Grant-in-Aids for SI, MO, MK and RU from the Ministry of Education, Culture, Sports, Science and Technology, and for SI and RU from the Ministry of Health, Labor and Welfare. SI is supported by a Grant of the Princess Takamatsu Cancer Research Fund.

Author information

Author notes

  1. T Sanda and T Kuwano: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    T Sanda, S Iida, T Ishida, H Komatsu & R Ueda

  2. Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    T Kuwano, S Nakao & M Ono

  3. Research Foundation ITSUU Laboratory, Tokyo, Japan

    K Shudo

  4. Center of Innovative Cancer Therapy, Kurume University, Kurume, Japan

    M Kuwano

Authors
  1. T Sanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Kuwano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Iida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Komatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Shudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Kuwano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Ueda.

Additional information

Supplementary Information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sanda, T., Kuwano, T., Nakao, S. et al. Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. Leukemia 19, 901–909 (2005). https://doi.org/10.1038/sj.leu.2403754

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403754

Keywords

This article is cited by

Search

Advanced search

Quick links