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.
authors.affiliation: Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kizaki
authors.forename: H
authors.initials: H
authors.lastname: Ueno
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazoe
authors.forename: M
authors.initials: M
authors.lastname: Shimada
authors.forename: N
authors.initials: N
authors.lastname: Takayama
authors.forename: A
authors.initials: A
authors.lastname: Muto
authors.forename: H
authors.initials: H
authors.lastname: Matsushita
authors.forename: H
authors.initials: H
authors.lastname: Nakajima
authors.forename: M
authors.initials: M
authors.lastname: Morikawa
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001483:Base Sequence; D001711:Biotransformation; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D040501:Calgranulin A; D040502:Calgranulin B; D002454:Cell Differentiation / Q000187:drug effects; D003022:Clotrimazole / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D006098:Granulocytes / Q000473:pathology; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008861:Microsomes / Q000201:enzymology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D014212:Tretinoin / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D065607:Cytochrome P-450 Enzyme Inhibitors; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D001189:Aryl Hydrocarbon Hydroxylases; D003022:Clotrimazole