scholarly journals Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells

2002 ◽  
Vol 99 (2) ◽  
pp. 292-298 ◽  
Author(s):  
Astrid A. Ruefli ◽  
David Bernhard ◽  
Kellie M. Tainton ◽  
Reinhard Kofler ◽  
Mark J. Smyth ◽  
...  
Keyword(s):  
Cell Death ◽  
Multidrug Resistance ◽  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid ◽  
P Glycoprotein

HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2378-2385 ◽  
Author(s):  
Astrid A. Ruefli ◽  
Mark J. Smyth ◽  
Ricky W. Johnstone
Keyword(s):  
Cell Death ◽  
Multidrug Resistance ◽  
Fas Ligand ◽  
Cytotoxic T Cell ◽  
Serum Starvation ◽  
Independent Manner ◽  
Glycoprotein P ◽  
Protein Levels ◽  
Cell Death Pathway ◽  
P Glycoprotein

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.

HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2378-2385 ◽  
Author(s):  
Astrid A. Ruefli ◽  
Mark J. Smyth ◽  
Ricky W. Johnstone
Keyword(s):  
Cell Death ◽  
Multidrug Resistance ◽  
Fas Ligand ◽  
Cytotoxic T Cell ◽  
Serum Starvation ◽  
Independent Manner ◽  
Glycoprotein P ◽  
Protein Levels ◽  
Cell Death Pathway ◽  
P Glycoprotein

Abstract 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.

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