Joray Mariana Belén, Villafañez Florencia, González María Laura, Crespo María Inés, Laiolo Jerónimo, Palacios Sara María, Bocco José Luis, Soria Gastón, Carpinella María Cecilia
Fine Chemicals and Natural Products Laboratory, School of Chemistry, Catholic University of Córdoba, Avda Armada Argentina 3555, X5016DHK Córdoba, Argentina.
CIBICI CONICET and Department of Clinical Biochemistry, Faculty of Chemical Science, National University of Córdoba, Haya de la Torre and Medina Allende, Córdoba, Argentina.
Food Chem Toxicol. 2017 Nov;109(Pt 2):888-897. doi: 10.1016/j.fct.2017.04.039. Epub 2017 Apr 29.
This work examines the antitumor activity of an isomeric mixture (1), composed of the limonoids meliartenin and its interchangeable isomer 12-hydroxyamoorastatin. The results obtained showed that 1 displayed outstanding cytotoxic activity against CCRF-CEM, K562, A549 and HCT116 cells, with a highly selective effect on the latter, with an IC value of 0.2 μM. Based on this finding, HCT116 cells were selected to study the mechanism of action of 1. Cell cycle analysis revealed that 1 induced sustained arrest in the S-phase, which was followed by the triggering of apoptotic cell death and reduced clonogenic capacity. This cytotoxicity was seen to be preceded by the upregulation of the tumor suppressor p53 and its target effector p21. In addition, it was found that p53 expression was required for efficient cell death induction, and thus that the toxicity of 1 relies mainly on p53-dependent mechanisms. Taken together, these findings position 1 as a potent antitumor agent, with potential for the development of novel chemotherapeutic drugs based on the induction of S-phase arrest.
本研究考察了一种由柠檬苦素和其可互换异构体12-羟基奥莫他汀组成的异构体混合物（1）的抗肿瘤活性。所得结果表明，1对CCRF-CEM、K562、A549和HCT116细胞表现出显著的细胞毒活性，对后者具有高度选择性作用，IC值为0.2 μM。基于这一发现，选择HCT116细胞来研究1的作用机制。细胞周期分析显示，1诱导细胞在S期持续停滞，随后引发凋亡性细胞死亡并降低克隆形成能力。这种细胞毒性在肿瘤抑制因子p53及其靶效应因子p21上调之前就已出现。此外，发现高效诱导细胞死亡需要p53表达，因此1的毒性主要依赖于p53依赖性机制。综上所述，这些发现表明1是一种有效的抗肿瘤药物，具有基于诱导S期停滞开发新型化疗药物的潜力。
