Laboratory of Food and Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain.
APC Microbiome Ireland & School of Microbiology, University College Cork, T12 YT20 Cork, Ireland.
Int J Mol Sci. 2022 Mar 5;23(5):2860. doi: 10.3390/ijms23052860.
Dietary (poly)phenols are extensively metabolized, limiting their anticancer activity. Exosomes (EXOs) are extracellular vesicles that could protect polyphenols from metabolism. Our objective was to compare the delivery to breast tissue and anticancer activity in breast cancer cell lines of free curcumin (CUR) and resveratrol (RSV) vs. their encapsulation in milk-derived EXOs (EXO-CUR and EXO-RSV). A kinetic breast tissue disposition was performed in rats. CUR and RSV were analyzed using UPLC-QTOF-MS and GC-MS, respectively. Antiproliferative activity was tested in MCF-7 and MDA-MB-231 breast cancer and MCF-10A non-tumorigenic cells. Cell cycle distribution, apoptosis, caspases activation, and endocytosis pathways were determined. CUR and RSV peaked in the mammary tissue (41 ± 15 and 300 ± 80 nM, respectively) 6 min after intravenous administration of EXO-CUR and EXO-RSV, but not with equivalent free polyphenol concentrations. Nanomolar EXO-CUR or EXO-RSV concentrations, but not free CUR or RSV, exerted a potent antiproliferative effect on cancer cells with no effect on normal cells. Significant (p < 0.05) cell cycle alteration and pro-apoptotic activity (via the mitochondrial pathway) were observed. EXO-CUR and EXO-RSV entered the cells primarily via clathrin-mediated endocytosis, avoiding ATP-binding cassette transporters (ABC). Milk EXOs protected CUR and RSV from metabolism and delivered both polyphenols to the mammary tissue at concentrations compatible with the fast and potent anticancer effects exerted in model cells. Milk EXOs enhanced the bioavailability and anticancer activity of CUR and RSV by acting as Trojan horses that escape from cancer cells’ ABC-mediated chemoresistance.
饮食（多）酚广泛代谢，限制了其抗癌活性。外泌体（EXO）是一种细胞外囊泡，可以保护多酚免受代谢。我们的目的是比较游离姜黄素（CUR）和白藜芦醇（RSV）及其在牛奶衍生的 EXO 中的包封（EXO-CUR 和 EXO-RSV）对乳腺癌细胞系的乳腺组织递送和抗癌活性。在大鼠中进行了动力学乳腺组织处置。使用 UPLC-QTOF-MS 和 GC-MS 分别分析 CUR 和 RSV。在 MCF-7 和 MDA-MB-231 乳腺癌和 MCF-10A 非致瘤细胞中测试了抗增殖活性。测定细胞周期分布、细胞凋亡、半胱天冬酶激活和内吞途径。静脉注射 EXO-CUR 和 EXO-RSV 后 6 分钟，CUR 和 RSV 分别在乳腺组织中达到峰值（41 ± 15 和 300 ± 80 nM），但等效游离多酚浓度则没有。纳米摩尔 EXO-CUR 或 EXO-RSV 浓度，但不是游离 CUR 或 RSV，对癌细胞具有强大的抗增殖作用，对正常细胞没有影响。观察到明显的（p < 0.05）细胞周期改变和促凋亡活性（通过线粒体途径）。EXO-CUR 和 EXO-RSV 主要通过网格蛋白介导的内吞作用进入细胞，避免了 ATP 结合盒转运蛋白（ABC）。牛奶 EXO 保护 CUR 和 RSV 免受代谢，并以与在模型细胞中发挥快速和强大抗癌作用相容的浓度将两种多酚递送到乳腺组织中。牛奶 EXO 通过充当逃避癌细胞 ABC 介导的化疗耐药性的特洛伊木马，增强了 CUR 和 RSV 的生物利用度和抗癌活性。
