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Title: HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance.
Austin Authors: Ruefli, A A;Smyth, Mark J;Johnstone, R W
Affiliation: Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 1-Apr-2000
Publication information: Blood; 95(7): 2378-85
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.
Gov't Doc #: 10733510
Journal: Blood
Type: Journal Article
Subjects: Acetamides.pharmacology
Apoptosis.drug effects
Caspase 9
Cytochrome c Group.metabolism
Drug Resistance, Multiple
Enzyme Activation.drug effects
Leukemia-Lymphoma, Adult T-Cell.metabolism.pathology
Mitochondria.drug effects.metabolism
Proto-Oncogene Proteins c-bcl-2.metabolism
Tumor Cells, Cultured
Appears in Collections:Journal articles

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