|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2378-2385
HMBA induces activation of a caspase-independent cell death
pathway to overcome P-glycoprotein-mediated multidrug resistance
Astrid A. Ruefli,
Mark J. Smyth, and
Ricky W. Johnstone
From the Austin Research Institute, Austin Hospital,
Heidelberg, Victoria, Australia.
Multidrug resistance (MDR) is often characterized by the expression
of P-glycoprotein (P-gp), a 170-kd ATP-dependent drug efflux protein.
As well as effluxing xenotoxins, functional P-gp can confer resistance
to caspase-dependent apoptosis induced by a range of different stimuli,
including Fas ligand, tumor necrosis factor, UV irradiation, and serum
starvation. However, P-gp-positive cells remain sensitive to
caspase-independent death induced by cytotoxic T-cell granule proteins,
perforin, and granzyme B. It is, therefore, possible that agents that
induce cell death in a caspase-independent manner might circumvent
P-gp-mediated MDR. We demonstrated here that hexamethylene bisacetamide
(HMBA) induced equivalent caspase-independent cell death in both
P-gp-positive and -negative cell lines at concentrations of 10 mmol/L
and above. The HMBA-induced death pathway was marked by release of
cytochrome c from the mitochondria and reduction of Bcl-2 protein
levels. In addition, we show that functional P-gp specifically inhibits the activation of particular caspases, such as caspases-8 and -3, whereas others, such as caspase-9, remain unaffected. These studies
greatly enhance our understanding of the molecular cell death events
that can be regulated by functional P-gp and highlight the potential
clinical use of drugs that function via a caspase-independent pathway
for the treatment of MDR tumors.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. M. Shareef, B. Brown, S. Shajahan, S. Sathishkumar, S. M. Arnold, M. Mohiuddin, M. M. Ahmed, and P. M. Spring
Lack of P-Glycoprotein Expression by Low-Dose Fractionated Radiation Results from Loss of Nuclear Factor-{kappa}B and NF-Y Activation in Oral Carcinoma Cells
Mol. Cancer Res.,
January 1, 2008;
6(1):
89 - 98.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Han, L. Li, S. Qiu, Q. Lu, Q. Pan, Y. Gu, J. Luo, and X. Hu
Shikonin circumvents cancer drug resistance by induction of a necroptotic death
Mol. Cancer Ther.,
May 1, 2007;
6(5):
1641 - 1649.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Turella, G. Filomeni, M. L. Dupuis, M. R. Ciriolo, A. Molinari, F. De Maria, M. Tombesi, M. Cianfriglia, G. Federici, G. Ricci, et al.
A Strong Glutathione S-Transferase Inhibitor Overcomes the P-glycoprotein-mediated Resistance in Tumor Cells: 6-(7-NITRO-2,1,3-BENZOXADIAZOL-4-YLTHIO)HEXANOL (NBDHEX) TRIGGERS A CASPASE-DEPENDENT APOPTOSIS IN MDR1-EXPRESSING LEUKEMIA CELLS
J. Biol. Chem.,
August 18, 2006;
281(33):
23725 - 23732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Kelly, N. J. Waterhouse, E. Cretney, K. A. Browne, S. Ellis, J. A. Trapani, and M. J. Smyth
Granzyme M Mediates a Novel Form of Perforin-dependent Cell Death
J. Biol. Chem.,
May 21, 2004;
279(21):
22236 - 22242.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Peart, K. M. Tainton, A. A. Ruefli, A. E. Dear, K. A. Sedelies, L. A. O'Reilly, N. J. Waterhouse, J. A. Trapani, and R. W. Johnstone
Novel Mechanisms of Apoptosis Induced by Histone Deacetylase Inhibitors
Cancer Res.,
August 1, 2003;
63(15):
4460 - 4471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-H. Miao and J. Ding
Transcription Factor c-Jun Activation Represses mdr-1 Gene Expression
Cancer Res.,
August 1, 2003;
63(15):
4527 - 4532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Poulaki, C. S. Mitsiades, A. M. Joussen, A. Lappas, B. Kirchhof, and N. Mitsiades
Constitutive Nuclear Factor-{kappa}B Activity Is Crucial for Human Retinoblastoma Cell Viability
Am. J. Pathol.,
December 1, 2002;
161(6):
2229 - 2240.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Ruefli, M. J. Ausserlechner, D. Bernhard, V. R. Sutton, K. M. Tainton, R. Kofler, M. J. Smyth, and R. W. Johnstone
The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species
PNAS,
September 4, 2001;
(2001)
191208598.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Johnstone, K. M. Tainton, A. A. Ruefli, C. J. Froelich, L. Cerruti, S. M. Jane, and M. J. Smyth
P-glycoprotein Does Not Protect Cells against Cytolysis Induced by Pore-forming Proteins
J. Biol. Chem.,
May 11, 2001;
276(20):
16667 - 16673.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Ruefli, M. J. Ausserlechner, D. Bernhard, V. R. Sutton, K. M. Tainton, R. Kofler, M. J. Smyth, and R. W. Johnstone
The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species
PNAS,
September 11, 2001;
98(19):
10833 - 10838.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
