|
|
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.
 Previous Article | Next Article 
Submitted June 29, 2005
Accepted August 13, 2005
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*
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
* Corresponding author; email: sloni01{at}emory.edu.
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 dependant, and IK-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/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. Methods: MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Results: 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. Conclusion: The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma cell death, and warrants further pre-clinical 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:
|
|
|
|
 
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]
|
|
|
|
|
