Mechanisms of retinoid resistance in leukemic cells

Possible role of cytochrome P450 and P-glycoprotein

Masahiro Kizaki, Hironori Ueno, Yasushi Yamazoe, Miki Shimada, Nobuyuki Takayama, Akihiro Muto, Hiromichi Matsushita, Hideaki Nakajima, Minoru Morikawa, H. Phillip Koeffler, Yasuo Ikeda

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)725-733
Number of pages9
JournalBlood
Volume87
Issue number2
Publication statusPublished - 1996 Jan 15
Externally publishedYes

Fingerprint

Retinoids
P-Glycoprotein
Tretinoin
Cytochrome P-450 Enzyme System
Acute Promyelocytic Leukemia
HL-60 Cells
Clotrimazole
Verapamil
CD11b Antigens
Genes
MDR Genes
Messenger RNA
Cytochrome P-450 CYP1A1
Cell growth
Microsomes
Granulocytes
Metabolism
Cell Differentiation
Cell Count
Cell Proliferation

ASJC Scopus subject areas

  • Hematology

Cite this

Kizaki, M., Ueno, H., Yamazoe, Y., Shimada, M., Takayama, N., Muto, A., ... Ikeda, Y. (1996). Mechanisms of retinoid resistance in leukemic cells: Possible role of cytochrome P450 and P-glycoprotein. Blood, 87(2), 725-733.

Mechanisms of retinoid resistance in leukemic cells : Possible role of cytochrome P450 and P-glycoprotein. / Kizaki, Masahiro; Ueno, Hironori; Yamazoe, Yasushi; Shimada, Miki; Takayama, Nobuyuki; Muto, Akihiro; Matsushita, Hiromichi; Nakajima, Hideaki; Morikawa, Minoru; Koeffler, H. Phillip; Ikeda, Yasuo.

In: Blood, Vol. 87, No. 2, 15.01.1996, p. 725-733.

Research output: Contribution to journalArticle

Kizaki, M, Ueno, H, Yamazoe, Y, Shimada, M, Takayama, N, Muto, A, Matsushita, H, Nakajima, H, Morikawa, M, Koeffler, HP & Ikeda, Y 1996, 'Mechanisms of retinoid resistance in leukemic cells: Possible role of cytochrome P450 and P-glycoprotein', Blood, vol. 87, no. 2, pp. 725-733.
Kizaki M, Ueno H, Yamazoe Y, Shimada M, Takayama N, Muto A et al. Mechanisms of retinoid resistance in leukemic cells: Possible role of cytochrome P450 and P-glycoprotein. Blood. 1996 Jan 15;87(2):725-733.
Kizaki, Masahiro ; Ueno, Hironori ; Yamazoe, Yasushi ; Shimada, Miki ; Takayama, Nobuyuki ; Muto, Akihiro ; Matsushita, Hiromichi ; Nakajima, Hideaki ; Morikawa, Minoru ; Koeffler, H. Phillip ; Ikeda, Yasuo. / Mechanisms of retinoid resistance in leukemic cells : Possible role of cytochrome P450 and P-glycoprotein. In: Blood. 1996 ; Vol. 87, No. 2. pp. 725-733.
@article{64f075d9a7ab45c1ae6d2a02ebccb5d9,
title = "Mechanisms of retinoid resistance in leukemic cells: Possible role of cytochrome P450 and P-glycoprotein",
abstract = "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.",
author = "Masahiro Kizaki and Hironori Ueno and Yasushi Yamazoe and Miki Shimada and Nobuyuki Takayama and Akihiro Muto and Hiromichi Matsushita and Hideaki Nakajima and Minoru Morikawa and Koeffler, {H. Phillip} and Yasuo Ikeda",
year = "1996",
month = "1",
day = "15",
language = "English",
volume = "87",
pages = "725--733",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "2",

}

TY - JOUR

T1 - Mechanisms of retinoid resistance in leukemic cells

T2 - Possible role of cytochrome P450 and P-glycoprotein

AU - Kizaki, Masahiro

AU - Ueno, Hironori

AU - Yamazoe, Yasushi

AU - Shimada, Miki

AU - Takayama, Nobuyuki

AU - Muto, Akihiro

AU - Matsushita, Hiromichi

AU - Nakajima, Hideaki

AU - Morikawa, Minoru

AU - Koeffler, H. Phillip

AU - Ikeda, Yasuo

PY - 1996/1/15

Y1 - 1996/1/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=13344295088&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13344295088&partnerID=8YFLogxK

M3 - Article

VL - 87

SP - 725

EP - 733

JO - Blood

JF - Blood

SN - 0006-4971

IS - 2

ER -