|
|
 Previous Article | Table of Contents | Next Article 
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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. H. Seedhouse, M. Grundy, P. White, Y. Li, J. Fisher, D. Yakunina, A. V. Moorman, T. Hoy, N. Russell, A. Burnett, et al.
Sequential Influences of Leukemia-Specific and Genetic Factors on P-Glycoprotein Expression in Blasts from 817 Patients Entered into the National Cancer Research Network Acute Myeloid Leukemia 14 and 15 Trials
Clin. Cancer Res.,
December 1, 2007;
13(23):
7059 - 7066.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Evseenko, P. Murthi, J. W. Paxton, G. Reid, B. S. Emerald, K. M. Mohankumar, P. E. Lobie, S. P. Brennecke, B. Kalionis, and J. A. Keelan
The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction
FASEB J,
November 1, 2007;
21(13):
3592 - 3605.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. E. Modrak, D. V. Gold, and D. M. Goldenberg
Sphingolipid targets in cancer therapy.
Mol. Cancer Ther.,
February 1, 2006;
5(2):
200 - 208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Modlich, O. S. Kustikova, M. Schmidt, C. Rudolph, J. Meyer, Z. Li, K. Kamino, N. von Neuhoff, B. Schlegelberger, K. Kuehlcke, et al.
Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis
Blood,
June 1, 2005;
105(11):
4235 - 4246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pazirandeh, M. Jondal, and S. Okret
Glucocorticoids Delay Age-Associated Thymic Involution through Directly Affecting the Thymocytes
Endocrinology,
May 1, 2004;
145(5):
2392 - 2401.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Minderman, K. L. O'Loughlin, L. Pendyala, and M. R. Baer
VX-710 (Biricodar) Increases Drug Retention and Enhances Chemosensitivity in Resistant Cells Overexpressing P-Glycoprotein, Multidrug Resistance Protein, and Breast Cancer Resistance Protein
Clin. Cancer Res.,
March 1, 2004;
10(5):
1826 - 1834.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Baum, J. Dullmann, Z. Li, B. Fehse, J. Meyer, D. A. Williams, and C. von Kalle
Side effects of retroviral gene transfer into hematopoietic stem cells
Blood,
March 15, 2003;
101(6):
2099 - 2113.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Burger, J. A. Foekens, M. P. Look, M. E. Meijer-van Gelder, J. G. M. Klijn, E. A. C. Wiemer, G. Stoter, and K. Nooter
RNA Expression of Breast Cancer Resistance Protein, Lung Resistance-related Protein, Multidrug Resistance-associated Proteins 1 and 2, and Multidrug Resistance Gene 1 in Breast Cancer: Correlation with Chemotherapeutic Response
Clin. Cancer Res.,
February 1, 2003;
9(2):
827 - 836.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho
Myelodysplastic Syndrome
Hematology,
January 1, 2003;
2003(1):
176 - 199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. A. Patel, M. J. Dunn, and A. Sorokin
Regulation of MDR-1 (P-glycoprotein) by Cyclooxygenase-2
J. Biol. Chem.,
October 4, 2002;
277(41):
38915 - 38920.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Baer, S. L. George, R. K. Dodge, K. L. O'Loughlin, H. Minderman, M. A. Caligiuri, J. Anastasi, B. L. Powell, J. E. Kolitz, C. A. Schiffer, et al.
Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720
Blood,
July 30, 2002;
100(4):
1224 - 1232.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wang, A. E. Giuliano, and M. C. Cabot
Enhanced de Novo Ceramide Generation through Activation of Serine Palmitoyltransferase by the P-Glycoprotein Antagonist SDZ PSC 833 in Breast Cancer Cells
Mol. Cancer Ther.,
July 1, 2002;
1(9):
719 - 726.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. D. Bunting
ABC Transporters as Phenotypic Markers and Functional Regulators of Stem Cells
Stem Cells,
January 1, 2002;
20(1):
11 - 20.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. S. Watts, B. W. Futscher, R. Isett, M. Gleason-Guzman, M. W. Kunkel, and S. E. Salmon
cDNA Microarray Analysis of Multidrug Resistance: Doxorubicin Selection Produces Multiple Defects in Apoptosis Signaling Pathways
J. Pharmacol. Exp. Ther.,
November 1, 2001;
299(2):
434 - 441.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Pyo, H. Choy, G. P. Amorino, J.-s. Kim, Q. Cao, S. K. Hercules, and R. N. DuBois
A Selective Cyclooxygenase-2 Inhibitor, NS-398, Enhances the Effect of Radiation in Vitro and in Vivo Preferentially on the Cells That Express Cyclooxygenase-2
Clin. Cancer Res.,
October 1, 2001;
7(10):
2998 - 3005.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Linenberger, T. Hong, D. Flowers, E. L. Sievers, T. A. Gooley, J. M. Bennett, M. S. Berger, L. H. Leopold, F. R. Appelbaum, and I. D. Bernstein
Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin
Blood,
August 15, 2001;
98(4):
988 - 994.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Pallis, M. Grundy, J. Turzanski, R. Kofler, and N. Russell
Mitochondrial membrane sensitivity to depolarization in acute myeloblastic leukemia is associated with spontaneous in vitro apoptosis, wild-type TP53, and vicinal thiol/disulfide status
Blood,
July 15, 2001;
98(2):
405 - 413.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Legrand, J.-Y. Perrot, G. Simonin, M. Baudard, and J.-P. Marie
JC-1: a very sensitive fluorescent probe to test Pgp activity in adult acute myeloid leukemia
Blood,
January 15, 2001;
97(2):
502 - 508.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
