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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4322-4329. Prepublished online as a Blood First Edition Paper on August 23, 2005; DOI 10.1182/blood-2005-06-2584. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-06-2584v1 106/13/4322    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 David, E. Articles by Lonial, S. Search for Related Content PubMed PubMed Citation Articles by David, E. Articles by Lonial, S. Related Collections Neoplasia Apoptosis Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT Ebenezer David, Shi-Yong Sun, Edmund K. Waller, Jing Chen, Fadlo R. Khuri, and Sagar Lonial From the Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA. The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple myeloma (MM) growth is IL-6 dependent, and IL-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma-cell killing. MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Combination therapy induced synergistic tumor-cell death in MM cell lines and primary MM plasma cells. Cell death was rapid and associated with increased caspase 3, 8, and 9 cleavage and concomitant down-regulation of p-AKT. Down-regulation of p-AKT was seen only in combination therapy and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild-type AKT, or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important, supporting bortezomib followed by lonafarnib as the optimal schedule. The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma-cell death and warrants further preclinical and clinical studies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Not all that glitters is gold Yair Gazitt Blood 2005 106: 4025-4026. [Full Text] [PDF] This article has been cited by other articles: G. Bisping, D. Wenning, M. Kropff, D. Gustavus, C. Muller-Tidow, M. Stelljes, G. Munzert, F. Hilberg, G. J. Roth, M. Stefanic, et al. Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3-Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma Clin. Cancer Res., January 15, 2009; 15(2): 520 - 531. [Abstract] [Full Text] [PDF] E. David, R. Sinha, J. Chen, S.-Y. Sun, J. L. Kaufman, and S. Lonial Perifosine Synergistically Enhances TRAIL-Induced Myeloma Cell Apoptosis via Up-Regulation of Death Receptors Clin. Cancer Res., August 15, 2008; 14(16): 5090 - 5098. [Abstract] [Full Text] [PDF] T. Raz, V. Nardi, M. Azam, J. Cortes, and G. Q. Daley Farnesyl transferase inhibitor resistance probed by target mutagenesis Blood, September 15, 2007; 110(6): 2102 - 2109. [Abstract] [Full Text] [PDF] K. Schafer-Hales, J. Iaconelli, J. P. Snyder, A. Prussia, J. H. Nettles, A. El-Naggar, F. R. Khuri, P. Giannakakou, and A. I. Marcus Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function Mol. Cancer Ther., April 1, 2007; 6(4): 1317 - 1328. [Abstract] [Full Text] [PDF] K. E. Krueger and S. Srivastava Posttranslational Protein Modifications: Current Implications for Cancer Detection, Prevention, and Therapeutics Mol. Cell. Proteomics, October 1, 2006; 5(10): 1799 - 1810. [Full Text] [PDF] T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF] C. Yu, B. B. Friday, J.-P. Lai, L. Yang, J. Sarkaria, N. E. Kay, C. A. Carter, L. R. Roberts, S. H. Kaufmann, and A. A. Adjei Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol. Cancer Ther., September 1, 2006; 5(9): 2378 - 2387. [Abstract] [Full Text] [PDF] M. Maggio, J. M. Guralnik, D. L. Longo, and L. Ferrucci Interleukin-6 in aging and chronic disease: a magnificent pathway. J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2006; 61(6): 575 - 584. [Abstract] [Full Text] [PDF]

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