SEARCH:   Advanced

Blood, 15 September 2004, Vol. 104, No. 6, pp. 1825-1832. Prepublished online as a Blood First Edition Paper on May 25, 2004; DOI 10.1182/blood-2003-12-4218. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4218v1 104/6/1825    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 Schmidmaier, R. Articles by Meinhardt, G. Search for Related Content PubMed PubMed Citation Articles by Schmidmaier, R. Articles by Meinhardt, G. Related Collections Neoplasia Cell Adhesion and Motility Cytoskeleton Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase Ralf Schmidmaier, Philipp Baumann, Meral Simsek, Farshid Dayyani, Bertold Emmerich, and Gerold Meinhardt From the Laboratory for Molecular Haematology and Oncology of the Department of Haematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, Munich, Germany. Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function–associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting geranylgeranyl transferase (GGTase) and Rho kinase by specific inhibitors (GGTI-298 and Y-27632), but not inhibition of farnesyl transferase (FTase) by FTI-277, showed similar reduction of CAM-DR. Addition of geranylgeranyl pyrophosphate (GG-PP), but not of farnesyl pyrophosphate (F-PP), was able to inhibit simvastatin-induced CAM-DR reversal. Our data suggest that the 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA)/GG-PP/Rho/Rho-kinase pathway mediates CAM-DR and that targeting this pathway may improve the efficacy of antimyeloma therapies by reduction of CAM-DR. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Reducing cholesterol and overcoming drug resistance Steven Grant Blood 2004 104: 1598-1599. [Full Text] [PDF] This article has been cited by other articles: Y. Hiruma, T. Honjo, D. F. Jelinek, J. J. Windle, J. Shin, G. D. Roodman, and N. Kurihara Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation Blood, May 14, 2009; 113(20): 4894 - 4902. [Abstract] [Full Text] [PDF] T. M. Tancred, A. R. Belch, T. Reiman, L. M. Pilarski, and J. Kirshner Altered Expression of Fibronectin and Collagens I and IV in Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance J. Histochem. Cytochem., March 1, 2009; 57(3): 239 - 247. [Abstract] [Full Text] [PDF] P. Baumann, S. Mandl-Weber, A. Volkl, C. Adam, I. Bumeder, F. Oduncu, and R. Schmidmaier Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells Mol. Cancer Ther., February 1, 2009; 8(2): 366 - 375. [Abstract] [Full Text] [PDF] C. Laezza, S. Pisanti, A. M. Malfitano, and M. Bifulco The anandamide analog, Met-F-AEA, controls human breast cancer cell migration via the RHOA/RHO kinase signaling pathway Endocr. Relat. Cancer, December 1, 2008; 15(4): 965 - 974. [Abstract] [Full Text] [PDF] S. Doublier, C. Riganti, C. Voena, C. Costamagna, E. Aldieri, G. Pescarmona, D. Ghigo, and A. Bosia RhoA Silencing Reverts the Resistance to Doxorubicin in Human Colon Cancer Cells Mol. Cancer Res., October 1, 2008; 6(10): 1607 - 1620. [Abstract] [Full Text] [PDF] C. Riganti, S. Doublier, C. Costamagna, E. Aldieri, G. Pescarmona, D. Ghigo, and A. Bosia Activation of Nuclear Factor-{kappa}B Pathway by Simvastatin and RhoA Silencing Increases Doxorubicin Cytotoxicity in Human Colon Cancer HT29 Cells Mol. Pharmacol., August 1, 2008; 74(2): 476 - 484. [Abstract] [Full Text] [PDF] Q. Chen, W. Xie, D. J. Kuhn, P. M. Voorhees, A. Lopez-Girona, D. Mendy, L. G. Corral, V. P. Krenitsky, W. Xu, L. Moutouh-de Parseval, et al. Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy Blood, May 1, 2008; 111(9): 4690 - 4699. [Abstract] [Full Text] [PDF] G. M. Hatch, Y. Gu, F. Y. Xu, J. Cizeau, S. Neumann, J.-S. Park, S. Loewen, and M. R.A. Mowat StARD13(Dlc-2) RhoGap Mediates Ceramide Activation of Phosphatidylglycerolphosphate Synthase and Drug Response in Chinese Hamster Ovary Cells Mol. Biol. Cell, March 1, 2008; 19(3): 1083 - 1092. [Abstract] [Full Text] [PDF] M. Kobune, H. Chiba, J. Kato, K. Kato, K. Nakamura, Y. Kawano, K. Takada, R. Takimoto, T. Takayama, H. Hamada, et al. Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism Mol. Cancer Ther., June 1, 2007; 6(6): 1774 - 1784. [Abstract] [Full Text] [PDF] W. W.-L. Wong, J. W. Clendening, A. Martirosyan, P. C. Boutros, C. Bros, F. Khosravi, I. Jurisica, A. K. Stewart, P. L. Bergsagel, and L. Z. Penn Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma Mol. Cancer Ther., June 1, 2007; 6(6): 1886 - 1897. [Abstract] [Full Text] [PDF] Y. Dai, P. Khanna, S. Chen, X.-Y. Pei, P. Dent, and S. Grant Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation Blood, May 15, 2007; 109(10): 4415 - 4423. [Abstract] [Full Text] [PDF] E. Sekimoto, S. Ozaki, T. Ohshima, H. Shibata, T. Hashimoto, M. Abe, N. Kimura, K. Hattori, S. Kawai, Y. Kinoshita, et al. A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment Cancer Res., February 1, 2007; 67(3): 1184 - 1192. [Abstract] [Full Text] [PDF] M. Chatterjee, S. Jain, T. Stuhmer, M. Andrulis, U. Ungethum, R.-J. Kuban, H. Lorentz, K. Bommert, M. Topp, D. Kramer, et al. STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90{alpha} and {beta} in multiple myeloma cells, which critically contribute to tumor-cell survival Blood, January 15, 2007; 109(2): 720 - 728. [Abstract] [Full Text] [PDF] Y. C. Li, M. J. Park, S.-K. Ye, C.-W. Kim, and Y.-N. Kim Elevated Levels of Cholesterol-Rich Lipid Rafts in Cancer Cells Are Correlated with Apoptosis Sensitivity Induced by Cholesterol-Depleting Agents Am. J. Pathol., April 1, 2006; 168(4): 1107 - 1118. [Abstract] [Full Text] [PDF] N. W.C.J. van de Donk, H. M. Lokhorst, E. H.J. Nijhuis, M. M.J. Kamphuis, and A. C. Bloem Geranylgeranylated Proteins are Involved in the Regulation of Myeloma Cell Growth Clin. Cancer Res., January 15, 2005; 11(2): 429 - 439. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020