title: Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells.
abstract: Recent studies have shown that a high proportion of patients with acute promyelocytic leukemia (APL) achieve complete remission after treatment with all-trans retinoic acid (RA). Nevertheless, despite an initial good response, most patients that received continuous treatment with all-trans RA relapse and develop RA-resistant disease. The 9-cis RA is a high-affinity ligand for retinoid X receptors (RXRs) and also binds efficiently to retinoic acid receptors (RARs); all-trans RA is a ligand for RARs. Both alone are able to induce differentiation of wild-type HL-60 cells. We found that neither all-trans RA nor 9-cis RA (< 2 x 10(-6) mol/L) induced differentiation of RA-resistant HL-60 cells into either mature granulocytes or monocytes. However, morphologic differentiation of the RA-resistant HL-60 cells was induced by 10(-6) mol/L all-trans RA combined with various concentrations (10(-12) to 10(-6) mol/L) of 9-cis RA. Electron microscopic examination also confirmed that the combination of both retinoids induced RA-resistant HL-60 cells to differentiate to mature granulocytes. Functional analysis of differentiation (NBT reduction activity) confirmed the necessity of both analogs to induce differentiation. Also, expression of myeloid-specific differentiation antigens (CD11b and CD14) as well as migration inhibitory factor-related protein (MRP)-8/14 mRNAs were upregulated only in the presence of both retinoids in a dose-dependent manner. In these conditions 3H-thymidine incorporation was inhibited and numbers of viable cells were decreased, suggesting that all-trans RA with 9-cis RA may inhibit cell growth and induce differentiation of RA-resistant HL-60 cells into mature granulocytes. These studies suggest that 9-cis RA in combination with all-trans RA is an effective inducer of RA-resistant HL-60 cells and may have implications for both the biology of retinoids and clinical treatment of RA-resistant acute myelogenous leukemia, including APL patients.
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: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Koike
authors.forename: M
authors.initials: M
authors.lastname: Morikawa
authors.forename: M
authors.initials: M
authors.lastname: Ohta
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D040501:Calgranulin A; D040502:Calgranulin B; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics; D013237:Stereoisomerism; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin