title: Enhancement of differentiation induction and upregulation of CCAAT/enhancer-binding proteins and PU.1 in NB4 cells treated with combination of ATRA and valproic acid.
abstract: The effects of all-trans retinoic acid (ATRA) and valproic acid (VPA), alone and in combination, on the human acute promyelocytic leukemia (APL) cell line NB4 were investigated in view of differentiation induction and growth inhibition. After 48 h of treatment, not only ATRA but also VPA induced differentiation in NB4 cells, and their combination further augmented the differentiation activity. Furthermore, the upregulation of transcription factors including CCAAT/enhancer-binding proteins (CEBPα, β, ε) and PU.1, which are known to be critical factors for normal myelopoiesis, granulocytic maturation and being repressed in APL, concurred with the differentiation induction. A significant cell growth inhibition was observed after the treatment with VPA, which was further strengthened by the addition of ATRA. Given the importance of C/EBPs and PU.1 in myeloid development, these results, thus, suggest that restoration of the normal function of the myeloid cell transcriptional machinery is a major molecular mechanism underlying the differentiation induction in NB4. Therefore, these results may provide novel insights into a possible combinational therapeutic approach for APL patients.
authors.affiliation: Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Iriyama
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yoshino
authors.affiliation: Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hatta
authors.affiliation: Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Horikoshi
authors.affiliation: Department of Functional Morphology, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Aizawa
authors.affiliation: Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Takei
authors.affiliation: Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Takeuchi
authors.affiliation: Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Takagi
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Toyoda
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis*; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D013256:Steroids / Q000008:administration & dosage; D015534:Trans-Activators / Q000096:biosynthesis*; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives; D014635:Valproic Acid / Q000008:administration & dosage; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000970:Antineoplastic Agents; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013256:Steroids; D015534:Trans-Activators; D014212:Tretinoin; D014635:Valproic Acid; D000099232:Proto-Oncogene Protein Spi-1; C559105:EA-4 (ATRA steroidal analog); C070790:CEBPE protein, human