Laboratorio de Patología y Farmacología Molecular, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.
Phytomedicine. 2012 Jun 15;19(8-9):737-46. doi: 10.1016/j.phymed.2012.03.008. Epub 2012 Apr 25.
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.
化疗是治疗白血病的主要方法。然而，由于不良副作用的发生和某些情况下的完全无效，开发新药物是必要的。作为我们评估天然香豆素潜在化疗效果的筛选计划的一部分，我们研究了从 Toddalia asiatica（芸香科）茎皮中分离得到的一系列六种prenylated coumarins 的抗白血病活性。在这些化合物中，6-(3-methyl-2-butenyl)-5,7-dimethoxycoumarin（toddaculin）在 U-937 细胞中显示出最强的细胞毒性和抗增殖作用。为了确定这些作用是否是由于诱导细胞死亡或分化所致，我们进一步评估了几种凋亡和成熟标志物的表达。有趣的是，虽然 toddaculin 在 250 μM 时能够诱导 U-937 细胞凋亡，涉及 ERK 和 Akt 的磷酸化水平降低，但 50 μM 的 toddaculin 具有分化作用，诱导 U-937 细胞减少 NBT 的能力和分化标志物 CD88 和 CD11b 的表达，但 p-Akt 或 p-ERK 水平没有变化。综上所述，这些发现表明 toddaculin 在 U-937 细胞中显示出作为细胞分化剂和凋亡诱导剂的双重作用，表明它可能作为开发新型抗白血病药物的药理学原型。
