Cedrelone is a limonoid isolated from the plant Trichilia catigua (Meliaceae). Previous studies have demonstrated that cedrelone (1) has several damaging effects on triple negative breast tumor (TNBC) cell line MDA-MB-231. In this work we investigated two new derivatives of cedrelone, the acetate (1a) and the mesylate (1b), to examine whether their effects are improved in comparison to the lead molecule. Cedrelone acetate (1a) was the most cytotoxic compound on TNBC cells and was chosen for additional analyses in traditional two-dimensional (2D) monolayer cultures and three-dimensional (3D) assays. In 2D, 1a induced cell cycle arrest, apoptosis and inhibited essential steps of the metastasis process of the MDA-MB-231 cells, in vitro. Moreover, 1a was able to revert the malignant phenotype of the T4-2 cells in 3D. These effects were concomitant with the downregulation of EGFR, β1-integrin and phospho-Akt, which could have resulted in a decrease of NFκB levels and MMP9 activity. These results suggest that 1a could be used as an important model for the design of a new drug to be applied in cancer treatment and be further studied in vivo for its antitumor and antimetastatic effects.

中文翻译：

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醋曲龙的乙酰化增加其细胞毒性活性，并逆转3D培养中乳腺癌细胞的恶性表型。

塞瑞隆是从植物毛T属（Meliaceae）中分离的柠檬苦素。先前的研究表明，塞德隆（1）对三阴性乳腺肿瘤（TNBC）细胞系MDA-MB-231具有多种破坏作用。在这项工作中，我们研究了西地龙的两种新衍生物，醋酸盐（1a）和甲磺酸盐（1b），以检查它们的作用与铅分子相比是否有所改善。醋酸塞德隆（1a）是TNBC细胞上最具细胞毒性的化合物，被选作传统二维（2D）单层培养和三维（3D）分析中的其他分析方法。在2D中，1a在体外诱导了MDA-MB-231细胞转移周期的停滞，凋亡并抑制了其转移过程的关键步骤。此外，1a能够逆转3D中T4-2细胞的恶性表型。这些作用与EGFR，β1-整合素和磷酸化Akt的下调同时发生，这可能导致NFκB水平和MMP9活性降低。这些结果表明1a可以用作设计用于癌症治疗的新药的重要模型，并在体内对其抗肿瘤和抗转移作用进行进一步研究。