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Mechanisms of retinoid resistance in leukemic cells: possible role of
cytochrome P450 and P-glycoprotein
M Kizaki, H Ueno, Y Yamazoe, M Shimada, N Takayama, A Muto, H Matsushita, H Nakajima, M Morikawa, HP Koeffler and Y Ikeda
Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
Retinoic acid (RA) regulates the differentiation and proliferation of a
wide variety of different cell types and all-trans RA induces complete
remission in a high proportion of patients with acute promyelocytic
leukemia (APL). However, clinical resistance to retinoids may develop and
poses a serious problem for differentiation-inducing therapy. We studied
the effects of RA in combination with a cytochrome P450 inhibitor
(clotrimazole) and a P-glycoprotein antagonist (verapamil) on cell growth
and differentiation of RA-resistant HL-60 cells and fresh RA-resistant
leukemic cells from two APL patients. RA-resistant HL-60 cells and APL
cells differentiated to mature granulocytes when cultured with all-trans RA
and either clotrimazole and verapamil but not with either of the agents
alone. These findings were confirmed in these cells by their increased
expression of CD11b antigen and migration- inhibitory factor-related
protein-8/14 mRNAs and decreased levels of c- myc mRNA. These combinations
also markedly decreased the number of viable cells and inhibited cellular
proliferation. After isolation of microsomes, measurements showed that
levels of cytochrome P450 activities in both wild-type and RA-resistant
HL-60 cells were almost comparable. Moreover, expression of the CYP1A1-type
cytochrome P450 gene could not be detected in either cell type. However,
RA-resistant HL-60 cells and APL cells, but not RA-sensitive HL-60 cells
and APL cells, expressed multidrug-resistance-1 gene transcripts. Taken
together, acquired resistance to RA may be explained in part by drug
metabolism in leukemic cells. Possible mechanisms for accelerated clearance
of RA include the induction of non-CYP1A1 cytochrome P450 enzymes and
P-glycoprotein.
Volume 87,
Issue 2,
pp. 725-733,
01/15/1996
Copyright © 1996 by The American Society of Hematology
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