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Title: | P-glycoprotein protects leukemia cells against caspase-dependent, but not caspase-independent, cell death. | Austin Authors: | Johnstone, R W;Cretney, E;Smyth, Mark J | Affiliation: | The Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia | Issue Date: | 1-Feb-1999 | Publication information: | Blood; 93(3): 1075-85 | Abstract: | A major problem with treating patients with cancer by traditional chemotherapeutic regimes is that their tumors often develop a multidrug resistant (MDR) phenotype and subsequently become insensitive to a range of different chemotoxic drugs. One cause of MDR is overexpression of the drug-effluxing protein, P-glycoprotein. It is now apparent that P-glycoprotein may also possess a more generic antiapoptotic function that protects P-glycoprotein-expressing cancer cells and normal cells from cell death. Herein we show that cells induced to express P-glycoprotein either by drug selection or by retroviral gene transduction with MDR1 cDNA are resistant to cell death induced by a wide range of death stimuli, such as FasL, tumor necrosis factor (TNF), and ultraviolet (UV) irradiation, that activate the caspase apoptotic cascade.However, P-glycoprotein-expressing cells were not resistant to caspase-independent cell death mediated by pore-forming proteins and granzyme B.MDR P-glycoprotein-expressing cells were made sensitive to caspase-dependent apoptosis by the addition of anti-P-glycoprotein antibodies or verapamil, a pharmacological inhibitor of P-glycoprotein function. Clonogenic assays showed that P-glycoprotein confers long-term resistance to caspase-dependent apoptotic stimuli but not to caspase-independent cell death stimuli. This study has confirmed a potential novel physiological function for P-glycoprotein and it now remains to dissect the molecular mechanisms involved in the inhibition of capsase-dependent cell death by P-glycoprotein. | Gov't Doc #: | 9920858 | URI: | http://ahro.austin.org.au/austinjspui/handle/1/13643 | Journal: | Blood | URL: | https://pubmed.ncbi.nlm.nih.gov/9920858 | Type: | Journal Article | Subjects: | Antibodies, Monoclonal.pharmacology Antigens, CD95.physiology Antineoplastic Agents.pharmacology Apoptosis.drug effects.physiology.radiation effects Caspases.physiology Cytotoxicity, Immunologic DNA, Complementary.genetics Dexamethasone.pharmacology Enzyme Inhibitors.pharmacology Etoposide.pharmacology Fas Ligand Protein Genes, MDR Granzymes Humans Leukemia-Lymphoma, Adult T-Cell.pathology Membrane Glycoproteins.pharmacology Neoplasm Proteins.physiology P-Glycoprotein.genetics.physiology Perforin Pore Forming Cytotoxic Proteins Recombinant Proteins.pharmacology Serine Endopeptidases.pharmacology Transfection Tumor Necrosis Factor-alpha.pharmacology Tumor Stem Cell Assay Ultraviolet Rays Verapamil.pharmacology Vinblastine.pharmacology |
Appears in Collections: | Journal articles |
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