title: Monocyte-macrophage differentiation of acute myeloid leukemia cell lines by small molecules identified through interrogation of the Connectivity Map database.
abstract: The transcription factor C/EBPα is required for granulocytic differentiation of normal myeloid progenitors and is frequently inactivated in acute myeloid leukemia (AML) cells. Ectopic expression of C/EBPα in AML cells suppresses proliferation and induces differentiation suggesting that restoring C/EBPα expression/activity in AML cells could be therapeutically useful. Unfortunately, current approaches of gene or protein delivery in leukemic cells are unsatisfactory. However, "drug repurposing" is becoming a very attractive strategy to identify potential new uses for existing drugs. In this study, we assessed the biological effects of candidate C/EBPα-mimetics identified by interrogation of the Connectivity Map database. We found that amantadine, an antiviral and anti-Parkinson agent, induced a monocyte-macrophage-like differentiation of HL60, U937, Kasumi-1 myeloid leukemia cell lines, as indicated by morphology and differentiation antigen expression, when used in combination with suboptimal concentration of all trans retinoic acid (ATRA) or Vit D3. The effect of amantadine depends, in part, on increased activity of the vitamin D receptor (VDR), since it induced VDR expression and amantadine-dependent monocyte-macrophage differentiation of HL60 cells was blocked by expression of dominant-negative VDR. These results reveal a new function for amantadine and support the concept that screening of the Connectivity Map database can identify small molecules that mimic the effect of transcription factors required for myelo-monocytic differentiation.
authors.affiliation: a Department of Diagnostic and Clinical Medicine and Public Health ; University of Modena and R. Emilia ; Modena , Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Manzotti
authors.forename: Sandra
authors.initials: S
authors.lastname: Parenti
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ferrari-Amorotti
authors.forename: Angela Rachele
authors.initials: AR
authors.lastname: Soliera
authors.forename: Sara
authors.initials: S
authors.lastname: Cattelani
authors.forename: Monica
authors.initials: M
authors.lastname: Montanari
authors.forename: Daniel
authors.initials: D
authors.lastname: Cavalli
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Alexis
authors.initials: A
authors.lastname: Grande
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D000547:Amantadine; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression; D018922:HL-60 Cells; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D060066:Protein Interaction Maps; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D010880:Piperidines; D018167:Receptors, Calcitriol; D013629:Tamoxifen; C027013:diperodon; D014212:Tretinoin; D000547:Amantadine; D007041:Hypoxanthine Phosphoribosyltransferase
keywords: cell cycle; differentiationm; leukemia; therapy; transcription factor