title: Rosmarinic acid potentiates ATRA-induced macrophage differentiation in acute promyelocytic leukemia NB4 cells.
abstract: Rosmarinic acid (RA, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid) has a number of biological activities, but little is known about anti-leukemic activities of RA combined with all-trans retinoic acid (ATRA) against acute promyelocytic leukemia (APL) cells. We examined the differentiation marker, CD11b, in bone marrow cells (BMC) of an APL patient, in NB4 cells (APL cell line), and in normal BMC and peripheral blood mononuclear cells (PBMC) of healthy subjects by flow cytometric analysis. ATRA/RA induced expression of CD11b in the BMC of the APL patient and in NB4 cells, but not in normal BMC or PBMC. Therefore, we realized that RA potentiated ATRA-induced macrophage differentiation in APL cells. Further characterization of the induced macrophages showed that they exhibited morphological changes and were able to phagocytose and generate reactive oxygen species. Th also had typical expression of C-C chemokine receptor type 1 (CCR1), CCR2, and intercellular adhesion molecule-1 (ICAM-1). Moreover, the expression of CD11b(+) and CD14(+) cells depended on ERK-NF-κB axis activation. Together, these results indicate that RA potentiates ATRA-induced macrophage differentiation in APL cells. Thus, RA may play an important role as an appurtenant differentiation agent for functional macrophage differentiation in APL. Additionally, the differentiated macrophages might have a normal life span and, they could die. These data indicate that co-treatment with RA and ATRA has potential as an anti-leukemic therapy in APL.
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea.
authors.forename: Sook-Kyoung
authors.initials: SK
authors.lastname: Heo
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Eui-Kyu
authors.initials: EK
authors.lastname: Noh
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea.
authors.forename: Dong-Joon
authors.initials: DJ
authors.lastname: Yoon
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Jae-Cheol
authors.initials: JC
authors.lastname: Jo
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: SuJin
authors.initials: S
authors.lastname: Koh
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Department of Hematology and Oncology, Myongji Hospital, Gyeonggi-do 412-270, Republic of Korea.
authors.forename: Jae-Hoo
authors.initials: JH
authors.lastname: Park
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea; Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Min
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea; Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea. Electronic address: kimhawkmd@gmail.com.
authors.forename: Hawk
authors.initials: H
authors.lastname: Kim
mesh_terms: D039481:CD11b Antigen / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D053630:Depsides / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D054389:Receptors, CCR1 / Q000235:genetics; D054390:Receptors, CCR2 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D000097123:Rosmarinic Acid
chemical_list: D039481:CD11b Antigen; D002934:Cinnamates; D053630:Depsides; D048049:Extracellular Signal-Regulated MAP Kinases; D018799:Intercellular Adhesion Molecule-1; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D014212:Tretinoin; D000097123:Rosmarinic Acid; C515300:CCR1 protein, human; C515334:CCR2 protein, human
keywords: Acute promyelocytic leukemia; All-trans retinoic acid; Anti-leukemic activity; Differentiation therapy; Macrophage differentiation; Rosmarinic acid; Rosmarinic acid (Pubchem CID 5281792).