Toddaculin, a natural coumarin from Toddalia asiatica, induces differentiation and apoptosis in U-937 leukemic cells

• Published in: Phytomedicine (Stuttgart) 2012-06, Vol.19 (8-9), p.737-746
• Main Authors: Vázquez, Ramiro, Riveiro, María E., Vermeulen, Mónica, Mondillo, Carolina, Coombes, Philip H., Crouch, Neil R., Ismail, Fathima, Mulholland, Dulcie A., Baldi, Alberto, Shayo, Carina, Davio, Carlos
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Care and treatment; Cell differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical properties; Coumarins; Coumarins - chemistry; Coumarins - pharmacology; Differentiating activity; Down-Regulation - drug effects; Drug Screening Assays, Antitumor; Extracellular Signal-Regulated MAP Kinases - metabolism; Health aspects; Humans; Leukemia; Leukemia - drug therapy; Leukemia - metabolism; Leukemia - pathology; MAP Kinase Kinase 4 - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rutaceae; Rutaceae - chemistry; Toddaculin; Toddalia asiatica
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2012.03.008

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 250μM was able to induce apoptosis in U-937 cells, involving decreased phosphorylation levels of ERK and Akt, 50μM 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.