Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 599-606
P-Glycoprotein Expression on Normal and Abnormally Expanded Natural
Killer Cells and Inhibition of P-Glycoprotein Function by Cyclosporin A
and Its Analogue, PSC833
Motoki Egashira,
Norihiko Kawamata,
Koichi Sugimoto,
Takako Kaneko, and
Kazuo Oshimi
From the Department of Hematology, Juntendo University School of
Medicine, Tokyo, Japan.
P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the
MDR1 gene, has been found to be expressed in many normal bone
marrow and peripheral blood cells. Among normal leukocytes, CD3
CD16+ or
CD3CD56+ lymphocytes, ie, natural killer
(NK) cells, express relatively high levels of P-gp, but little is known
about P-gp in abnormally expanded NK cells. In this study, we examined
the expression and activity of P-gp on NK cells derived from three
normal donors, six patients with indolent NK cell-lineage granular
lymphocyte-proliferative disorder (NK-GLPD), three patients with
aggressive NK cell tumors (one NK cell leukemia and two nasal NK cell
lymphoma), and two NK cell lines. By flow cytometric analysis using the
monoclonal antibody (MoAb) MRK16 and rhodamine 123 dye (Rh123), P-gp
expression and the efflux of Rh123 were found in all NK samples except
one NK cell line. The Rh123 efflux of NK cells was inhibited by
cyclosporin A (CsA) and its analogue PSC 833, but the aggressive NK
tumor cells were less inhibited than were the other NK cells. The
percent inhibition of efflux in the normal NK cells, indolent NK-GLPD cells and aggressive NK cell tumors was 81.8% ± 0.9%, 93.4% ± 3.1% and 36.9% ± 11.7%, respectively, by 1 µmol/L CsA, and
80.2% ± 3.6%, 91.7% ± 2.6% and 32.7% ± 10.1%, respectively,
by 1 µmol/L PSC833. In reverse transcription-polymerase chain
reaction (RT-PCR) analysis, the low inhibitory effect of P-gp
modulators in aggressive NK cell tumors did not correlate to the
expression level of MDR1 gene, multidrug resistance-associated
protein gene, or human canalicular multispecific organic anion
transporter gene. This phenomenon could be related to the presence of
other transporters or to unknown cellular or membrane changes. Some
patients with NK cell tumors have been reported to show a highly
aggressive clinical course and to be refractory to chemotherapy, and
this could be related to the expression of P-gp on NK cells. Our
results suggest that, although the inhibitors for P-gp have been used
in combination with chemotherapy in some hematologic tumors, these
inhibitors may be less effective against aggressive NK cell tumors.
