title: Toddaculin, a natural coumarin from Toddalia asiatica, induces differentiation and apoptosis in U-937 leukemic cells.
abstract: Chemotherapeutics represent the main approach for the treatment of leukemia. However, the occurrence of adverse side effects and the complete lack of effectiveness in some cases make it necessary to develop new drugs. As part of our screening program to evaluate the potential chemotherapeutic effect of natural coumarins, we investigated the anti-leukemic activities of a series of six prenylated coumarins isolated from the stem bark of Toddalia asiatica (Rutaceae). Among these, 6-(3-methyl-2-butenyl)-5,7-dimethoxycoumarin (toddaculin) displayed the most potent cytotoxic and anti-proliferative effects in U-937 cells. To determine whether these effects resulted from induction of cell death or differentiation, we further evaluated the expression of several apoptosis and maturation markers. Interestingly, while toddaculin at 250 μM was able to induce apoptosis in U-937 cells, involving decreased phosphorylation levels of ERK and Akt, 50 μM toddaculin exerted differentiating effects, inducing both the capacity of U-937 cells to reduce NBT and the expression of differentiation markers CD88 and CD11b, but no change in p-Akt or p-ERK levels. Taken together, these findings indicate that toddaculin displays a dual effect as a cell differentiating agent and apoptosis inducer in U-937 cells, suggesting it may serve as a pharmacological prototype for the development of novel anti-leukemic agents.
authors.affiliation: Laboratorio de Patología y Farmacología Molecular, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina. ramirobioq@hotmail.com
authors.forename: Ramiro
authors.initials: R
authors.lastname: Vázquez
authors.forename: María E
authors.initials: ME
authors.lastname: Riveiro
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Carolina
authors.initials: C
authors.lastname: Mondillo
authors.forename: Philip H
authors.initials: PH
authors.lastname: Coombes
authors.forename: Neil R
authors.initials: NR
authors.lastname: Crouch
authors.forename: Fathima
authors.initials: F
authors.lastname: Ismail
authors.forename: Dulcie A
authors.initials: DA
authors.lastname: Mulholland
authors.forename: Alberto
authors.initials: A
authors.lastname: Baldi
authors.forename: Carina
authors.initials: C
authors.lastname: Shayo
authors.forename: Carlos
authors.initials: C
authors.lastname: Davio
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D027821:Rutaceae / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; C576564:toddaculin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4