Guo Hui, Liu Dongmei, Gao Bin, Zhang Xiaohui, You Minli, Ren Hui, Zhang Hongbo, Santos Hélder A, Xu Feng
Department of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
Molecules. 2016 Jul 21;21(7):954. doi: 10.3390/molecules21070954.
Evodiamine (EVO) and rutaecarpine (RUT) are promising anti-tumor drug candidates. The evaluation of the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids of cancer cells would better recapitulate the native situation and thus better reflect an in vivo response to the treatment. Herein, we employed the 3D culture of MCF-7 and SMMC-7721 cells based on hanging drop method and evaluated the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids, and compared the results with those obtained from 2D monolayers. The drugs' IC50 values were significantly increased from the range of 6.4-44.1 μM in 2D monolayers to 21.8-138.0 μM in 3D multicellular spheroids, which may be due to enhanced mass barrier and reduced drug penetration in 3D models. The fluorescence of EVO and RUT was measured via fluorescence spectroscopy and the cellular uptake of both drugs was characterized in 2D tumor models. The results showed that the cellular uptake concentrations of RUT increased with increasing drug concentrations. However, the EVO concentrations uptaken by the cells showed only a small change with increasing drug concentrations, which may be due to the different solubility of EVO and Rut in solvents. Overall, this study provided a new vision of the anti-tumor activity of EVO and RUT via 3D multicellular spheroids and cellular uptake through the fluorescence of compounds.
吴茱萸碱（EVO）和吴茱萸次碱（RUT）是很有前景的抗肿瘤候选药物。评估EVO和RUT在癌细胞的三维多细胞球体中的抗增殖活性和细胞摄取情况，将能更好地重现天然状态，从而更好地反映体内对治疗的反应。在此，我们基于悬滴法对MCF-7和SMMC-7721细胞进行三维培养，并评估EVO和RUT在三维多细胞球体中的抗增殖活性和细胞摄取情况，并将结果与二维单层培养所获得的结果进行比较。药物的IC50值从二维单层培养中的6.4 - 44.1 μM显著增加到三维多细胞球体中的21.8 - 138.0 μM，这可能是由于三维模型中质量屏障增强和药物渗透减少所致。通过荧光光谱法测量EVO和RUT的荧光，并在二维肿瘤模型中表征两种药物的细胞摄取情况。结果表明，RUT的细胞摄取浓度随药物浓度增加而增加。然而，细胞摄取的EVO浓度随药物浓度增加仅显示出微小变化，这可能是由于EVO和Rut在溶剂中的溶解度不同所致。总体而言，本研究通过三维多细胞球体以及通过化合物荧光进行细胞摄取，为EVO和RUT的抗肿瘤活性提供了新的视角。
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