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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2897-2904
P-glycoprotein plays a drug-efflux-independent role in augmenting
cell survival in acute myeloblastic leukemia and is associated with
modulation of a sphingomyelin-ceramide apoptotic pathway
Monica Pallis and
Nigel Russell
From the Division of Haematology, School of Clinical and Laboratory
Sciences, University of Nottingham, and the Nottingham City Hospital,
Nottingham, UK.
P-glycoprotein (pgp), which is the product of the MDR1
(multidrug resistance-1) gene, has an established role as
a mediator of cytotoxic drug resistance in acute myeloid leukemia
(AML). To study the role of pgp in mediating apoptosis resistance in AML cells deprived of serum and growth factors, apoptosis was quantified by flow cytometry using uptake of the dye
7-amino-actinomycin D (7-AAD) alongside low forward scatter. In
pgp+ve primary AML samples, there was a significant increase in
apoptosis in the presence of the pgp-specific antibody UIC2 (mean
increase: 58%; range: 11%-95%; P < .05). Likewise,
apoptosis in growth factor-deprived TF1 cells cultured for 30 hours
increased 2.5-fold in the presence of 25 µg/mL UIC2. The pgp reversal
agent PSC-833 (1 µmol/L) augmented in vitro apoptosis by a median of
52% in pgp+ve patient samples and to a comparable degree in 6 pgp ve samples. To determine whether the sphingomyelin-ceramide
(SM-ceramide) pathway of apoptosis occurs in AML blasts in response to
cytotoxic drugs, cells were incubated with daunorubicin at the
patient-specific IC30 (the concentration of daunorubicin
that caused apoptotic cell death in 30% of cells) in the presence of
the ceramide synthase inhibitor fumonisin B1, which inhibited apoptosis
by 18%-81% (median: 40%). Exogenous SM failed to augment apoptosis
induced by growth factor withdrawal in pgp+ve TF1 cells and
was significantly more effective at augmenting apoptosis in pgpve
patient blasts (median increase in cell death: 33%; range: 19%-88%)
than in pgp+ve samples (median: 7%; range: 0%-27%;
P = .028). Cellular accumulation of exogenous SM was
associated with apoptosis and also occurred in nonapoptotic patient
cells treated with PSC-833. However, this effect was not seen following
treatment with the UIC2 antibody. These results indicate that pgp is
able to exert a protective effect on AML cell viability and that this
is associated with a reduced effect of exogenous SM on apoptosis. The
pgp reversal agent PSC-833 acts, at least in part, by a pgp independent
mechanism to alter SM distribution and to augment apoptosis induced in
AML cells by serum and growth factor withdrawal.
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