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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1075-1085
P-Glycoprotein Protects Leukemia Cells Against Caspase-Dependent,
but not Caspase-Independent, Cell Death
Ricky W. Johnstone,
Erika Cretney, and
Mark J. Smyth
From The Austin Research Institute, Austin Hospital, Heidelberg,
Victoria, Australia.
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.
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