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Blood, 15 January 2006, Vol. 107, No. 2, pp. 669-678. Prepublished online as a Blood First Edition Paper on September 15, 2005; DOI 10.1182/blood-2005-01-0306. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-01-0306v1 107/2/669    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Strömberg, T. Articles by Jernberg-Wiklund, H. Search for Related Content PubMed PubMed Citation Articles by Strömberg, T. Articles by Jernberg-Wiklund, H. Related Collections Neoplasia Apoptosis Cell Cycle Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells Thomas Strömberg, Simon Ekman, Leonard Girnita, Lina Y. Dimberg, Olle Larsson, Magnus Axelson, Johan Lennartsson, Ulf Hellman, Kristina Carlson, Anders Österborg, Karin Vanderkerken, Kenneth Nilsson, and Helena Jernberg-Wiklund From the Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; the Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden; the Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden; the Ludwig Institute for Cancer Research, Uppsala Biomedical Center (BMC), Uppsala, Sweden; the Department of Hematology, University Hospital, Uppsala, Sweden; the Department of Hematology and Oncology, Karolinska Hospital, Stockholm, Sweden; and the Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium. Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R -chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G2/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. A. Economou, S. Andersson, D. Vasilcanu, C. All-Ericsson, E. Menu, A. Girnita, L. Girnita, M. Axelson, S. Seregard, and O. Larsson Oral Picropodophyllin (PPP) Is Well Tolerated In Vivo and Inhibits IGF-1R Expression and Growth of Uveal Melanoma Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2337 - 2342. [Abstract] [Full Text] [PDF] M. A. Economou, J. Wu, D. Vasilcanu, L. Rosengren, C. All-Ericsson, I. van der Ploeg, E. Menu, L. Girnita, M. Axelson, O. Larsson, et al. Inhibition of VEGF Secretion and Experimental Choroidal Neovascularization by Picropodophyllin (PPP), an Inhibitor of the Insulin-like Growth Factor-1 Receptor Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2620 - 2626. 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Shoshan, and R. S. Gupta Picropodophyllotoxin or Podophyllotoxin Does Not Induce Cell Death via Insulin-like Growth Factor-I Receptor Cancer Res., March 15, 2007; 67(6): 2899 - 2899. [Full Text] [PDF] L. Conti, G. Regis, A. Longo, P. Bernabei, R. Chiarle, M. Giovarelli, and F. Novelli In the absence of IGF-1 signaling, IFN-{gamma} suppresses human malignant T-cell growth Blood, March 15, 2007; 109(6): 2496 - 2504. [Abstract] [Full Text] [PDF] H. Zhang, A. M. Pelzer, D. T. Kiang, and D. Yee Down-regulation of Type I Insulin-like Growth Factor Receptor Increases Sensitivity of Breast Cancer Cells to Insulin Cancer Res., January 1, 2007; 67(1): 391 - 397. [Abstract] [Full Text] [PDF] O. Landgren, Y. Zhang, S. H. Zahm, P. Inskip, T. Zheng, and D. Baris Risk of Multiple Myeloma following Medication Use and Medical Conditions: A Case-Control Study in Connecticut Women Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2342 - 2347. [Abstract] [Full Text] [PDF] J Riedemann and V M Macaulay IGF1R signalling and its inhibition Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S33 - S43. [Abstract] [Full Text] [PDF] A. Girnita, C. All-Ericsson, M. A. Economou, K. Astrom, M. Axelson, S. Seregard, O. Larsson, and L. Girnita The Insulin-Like Growth Factor-I Receptor Inhibitor Picropodophyllin Causes Tumor Regression and Attenuates Mechanisms Involved in Invasion of Uveal Melanoma Cells Clin. Cancer Res., February 15, 2006; 12(4): 1383 - 1391. [Abstract] [Full Text] [PDF] E. Menu, H. Jernberg-Wiklund, T. Stromberg, H. De Raeve, L. Girnita, O. Larsson, M. Axelson, K. Asosingh, K. Nilsson, B. Van Camp, et al. Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model Blood, January 15, 2006; 107(2): 655 - 660. [Abstract] [Full Text] [PDF]

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