|
|
Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-10-3067.
 Previous Article | Table of Contents | Next Article 
Blood, 15 May 2003, Vol. 101, No. 10, pp. 4105-4114
NEOPLASIA
Potentiation of dexamethasone-, paclitaxel-, and
Ad-p53-induced apoptosis by Bcl-2 antisense oligodeoxynucleotides in
drug-resistant multiple myeloma cells
Qun Liu and
Yair Gazitt
From the University of Texas Health Science Center,
San Antonio.
Overexpression of Bcl-2 in myeloma cells results in resistance to
drugs such as dexamethasone (DEX), adenovirus-mediated delivery of p53
(Ad-p53), and paclitaxel (TAX), which work through the intrinsic
apoptotic pathway. Bcl-2 antisense oligodeoxynucleotides (Bcl-2-ASO)
have been shown to induce apoptosis in cancer cells, as a single agent
or, better, in combination with chemotherapy. We hypothesized that
down-regulation of Bcl-2 by Bcl-2-ASO will sensitize drug-resistant
myeloma cells to undergo apoptosis. In this paper we report a detailed
time/dose study of the effect of Bcl-2-ASO on myeloma cells with
varying levels of Bcl-2. Treatment of myeloma cells expressing
relatively low levels of Bcl-2 with Bcl-2-ASO resulted in a substantial
apoptosis concomitant with a substantial depletion of Bcl-2 protein.
Maximal apoptosis was observed at 5 to 10 µg/mL Bcl-2-ASO, following
4 days of treatment. Down-regulation of Bcl-2 and apoptosis were time
and dose dependent and were sequence specific. In these cell lines,
apoptosis was accompanied by activation of caspase-9 and caspase-3 and
by release of cytochrome c to the cytosol. In contrast,
high Bcl-2-expressing myeloma cells were practically resistant to
Bcl-2-ASO. Most important, however, pretreatment of myeloma cells
expressing high levels of Bcl-2 with Bcl-2-ASO increased the extent of
DEX-, TAX-, and Ad-p53-induced apoptosis from 10%-20% to 70%-90%.
Increased apoptosis was accompanied by additional decrease in Bcl-2
protein. Similar results for down-regulation of Bcl-2 and apoptosis
were obtained with freshly isolated myeloma cells. These data support
development of clinical trials with combinations of Bcl-2-ASO and DEX,
TAX, or Ad-p53 in the treatment of refractory myeloma patients.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. Zhang, A. Suvannasankha, C. D. Crean, V. L. White, A. Johnson, C.-S. Chen, and S. S. Farag
OSU-03012, a Novel Celecoxib Derivative, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanisms
Clin. Cancer Res.,
August 15, 2007;
13(16):
4750 - 4758.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Kardosh, N. Soriano, Y.-T. Liu, J. Uddin, N. A. Petasis, F. M. Hofman, T. C. Chen, and A. H. Schonthal
Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib
Blood,
December 15, 2005;
106(13):
4330 - 4338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Z. Badros, O. Goloubeva, A. P. Rapoport, B. Ratterree, N. Gahres, B. Meisenberg, N. Takebe, M. Heyman, J. Zwiebel, H. Streicher, et al.
Phase II Study of G3139, a Bcl-2 Antisense Oligonucleotide, in Combination With Dexamethasone and Thalidomide in Relapsed Multiple Myeloma Patients
J. Clin. Oncol.,
June 20, 2005;
23(18):
4089 - 4099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Chanan-Khan, R. Niesvizky, R. J. Hohl, T. M. Zimmerman, N. P. Christiansen, G. J. Schiller, S. Smith, and S. Frankel
Randomized Multicenter Phase 3 Trial of High-Dose Dexamethasone (dex) with or without Oblimersen Sodium (G3139; Bcl-2 antisense; Genasense) for Patients with Advanced Multiple Myeloma (MM).
Blood (ASH Annual Meeting Abstracts),
November 16, 2004;
104(11):
1477 - 1477.
[Abstract]
|
|
|
|
|
|
|
P. J. Real, Y. Cao, R. Wang, Z. Nikolovska-Coleska, J. Sanz-Ortiz, S. Wang, and J. L. Fernandez-Luna
Breast Cancer Cells Can Evade Apoptosis-Mediated Selective Killing by a Novel Small Molecule Inhibitor of Bcl-2
Cancer Res.,
November 1, 2004;
64(21):
7947 - 7953.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-H. Jang and Y.-J. Surh
Bcl-2 Attenuation of Oxidative Cell Death Is Associated with Up-regulation of {gamma}-Glutamylcysteine Ligase via Constitutive NF-{kappa}B Activation
J. Biol. Chem.,
September 10, 2004;
279(37):
38779 - 38786.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sonnemann, V. Gekeler, A. Sagrauske, C. Muller, H.-P. Hofmann, and J. F. Beck
Down-regulation of protein kinase C{eta} potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells
Mol. Cancer Ther.,
July 1, 2004;
3(7):
773 - 781.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Evens, S. Prachand, B. Shi, M. Paniaqua, L. I. Gordon, and R. B. Gartenhaus
Imexon-Induced Apoptosis in Multiple Myeloma Tumor Cells Is Caspase-8 Dependent
Clin. Cancer Res.,
February 15, 2004;
10(4):
1481 - 1491.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Sunters, S. Fernandez de Mattos, M. Stahl, J. J. Brosens, G. Zoumpoulidou, C. A. Saunders, P. J. Coffer, R. H. Medema, R. C. Coombes, and E. W.-F. Lam
FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines
J. Biol. Chem.,
December 12, 2003;
278(50):
49795 - 49805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot
Advances in Biology and Therapy of Multiple Myeloma
Hematology,
January 1, 2003;
2003(1):
248 - 278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
