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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 (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 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 Stromberg, T. Articles by Jernberg-Wiklund, H. Search for Related Content PubMed PubMed Citation Articles by Stromberg, T. Articles by Jernberg-Wiklund, H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 24, 2005 Accepted August 26, 2005 IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells Thomas Stromberg, Simon Ekman, Leonard Girnita, Lina Y Dimberg, Olle Larsson, Magnus Axelson, Johan Lennartsson, Ulf Hellman, Kristina Carlson, Anders Osterborg, Karin Vanderkerken, Kenneth Nilsson, and Helena Jernberg-Wiklund* Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden Ludwig Institute for Cancer Research, Uppsala Biomedical Center (BMC), Uppsala, Sweden Department of Hematology, University Hospital, Uppsala, Sweden Department of Hematology and Oncology, Karolinska Hospital, Stockholm, Sweden Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium * Corresponding author; email: helena.jernberg_wiklund{at}genpat.uu.se. 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 MM patients. 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 downregulated 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: S. Yin, A. Girnita, T. Stromberg, Z. Khan, S. Andersson, H. Zheng, C. Ericsson, M. Axelson, M. Nister, O. Larsson, et al. Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma Neuro Oncology, October 20, 2009; (2009) nop008v1. [Abstract] [Full Text] [PDF] P. Shi, R. Lai, Q. Lin, A. S. Iqbal, L. C. Young, L. W. Kwak, R. J. Ford, and H. M. 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