|
|
Blood, 1 October 2005, Vol. 106, No. 7, pp. 2513-2519.
Prepublished online as a Blood First Edition Paper on June 21, 2005; DOI 10.1182/blood-2005-04-1678.
 Previous Article | Next Article 
Submitted April 26, 2005
Accepted June 2, 2005
Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death
Rong Chen, Michael J Keating, Varsha Gandhi, and William Plunkett*
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
* Corresponding author; email: wplunket{at}mdanderson.org.
Flavopiridol is active against CLL cells in vitro and in the treatment of advanced stage disease, but the mechanisms of these actions remain unclear. Originally developed as a general cyclin-dependent kinase inhibitor, flavopiridol is a potent transcriptional suppressor through the inhibition of P-TEFb (CDK9/cyclin T). P-TEFb phosphorylates the C-terminal domain (CTD) of RNA polymerase II to promote transcriptional elongation. Because most CLL cells are not actively cycling, and their viability is dependent upon the continuous expression of anti-apoptotic proteins, we hypothesized that flavopiridol induces apoptosis in CLL cells through the transcriptional down-regulation of such proteins. This study demonstrated that flavopiridol inhibited the phosphorylation of the CTD of RNA polymerase II in primary CLL cells and reduced RNA synthesis. This was associated with a decline of the transcripts and the levels of short-lived anti-apoptotic proteins such as Mcl-1 and XIAP, and resulted in the induction of apoptosis. The Bcl-2 protein level remained stable, although its mRNA was consistently reduced, suggesting that the outcome of transcription inhibition by flavopiridol is governed by the intrinsic stability of the individual transcripts and proteins. The dependence of CLL cell survival on short-lived oncoproteins may provide the biochemical basis for the therapeutic index in response to flavopiridol.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Fighting CLL cells: deciphering the enemy
- Emili Montserrat
Blood 2005 106: 2226.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
B. Z. Carter, D. H. Mak, W. D. Schober, M. F. Dietrich, C. Pinilla, L. T. Vassilev, J. C. Reed, and M. Andreeff
Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5
Blood,
April 1, 2008;
111(7):
3742 - 3750.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-R. A. Hussain, D. M. Lucas, A. J. Johnson, T. S. Lin, A. P. Bakaletz, V. X. Dang, S. Viatchenko-Karpinski, A. S. Ruppert, J. C. Byrd, P. Kuppusamy, et al.
Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium
Blood,
March 15, 2008;
111(6):
3190 - 3199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Rixe and T. Fojo
Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient?
Clin. Cancer Res.,
December 15, 2007;
13(24):
7280 - 7287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Stellrecht, C. J. Phillip, F. Cervantes-Gomez, and V. Gandhi
Multiple Myeloma Cell Killing by Depletion of the MET Receptor Tyrosine Kinase
Cancer Res.,
October 15, 2007;
67(20):
9913 - 9920.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Berro, C. de la Fuente, Z. Klase, K. Kehn, L. Parvin, A. Pumfery, E. Agbottah, A. Vertes, S. Nekhai, and F. Kashanchi
Identifying the Membrane Proteome of HIV-1 Latently Infected Cells
J. Biol. Chem.,
March 16, 2007;
282(11):
8207 - 8218.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. R. Rosato, J. A. Almenara, S. S. Kolla, S. C. Maggio, S. Coe, M. S. Gimenez, P. Dent, and S. Grant
Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions
Mol. Cancer Ther.,
February 1, 2007;
6(2):
692 - 702.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chen, Y. Dai, H. Harada, P. Dent, and S. Grant
Mcl-1 Down-regulation Potentiates ABT-737 Lethality by Cooperatively Inducing Bak Activation and Bax Translocation
Cancer Res.,
January 15, 2007;
67(2):
782 - 791.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Chen, V. Gandhi, and W. Plunkett
A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia.
Cancer Res.,
November 15, 2006;
66(22):
10959 - 10966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Cai, V. M. Latham Jr., X. Zhang, and G. I. Shapiro
Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells.
Cancer Res.,
September 15, 2006;
66(18):
9270 - 9280.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Gao, L. Kramer, M. Rahmani, P. Dent, and S. Grant
The Three-Substituted Indolinone Cyclin-Dependent Kinase 2 Inhibitor 3-[1-(3H-Imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) Kills Human Leukemia Cells via Down-Regulation of Mcl-1 through a Transcriptional Mechanism
Mol. Pharmacol.,
August 1, 2006;
70(2):
645 - 655.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. I. Shapiro
Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment
J. Clin. Oncol.,
April 10, 2006;
24(11):
1770 - 1783.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. K. Radhakrishnan and A. L. Gartel
A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits antiangiogenic activity.
Cancer Res.,
March 15, 2006;
66(6):
3264 - 3270.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
