Discipline of Pharmacy, Graduate School of Health, The University of Technology Sydney, NSW, Australia.
School of Mathematical and Physical Sciences, Faculty of Science, The University of Technology Sydney, NSW, Australia.
Acta Pharmacol Sin. 2017 Oct;38(10):1353-1368. doi: 10.1038/aps.2016.170. Epub 2017 Aug 31.
Organosulfur compounds derived from Allium vegetables have long been recognized for various therapeutic effects, including anticancer activity. Allicin, one of the main biologically active components of garlic, shows promise as an anticancer agent; however, instability makes it unsuitable for clinical application. The aim of this study was to investigate the effect of stabilized allicin derivatives on human breast cancer cells in vitro. In this study, a total of 22 stabilized thiosulfinate derivatives were synthesized and screened for their in vitro antiproliferative activities against drug-sensitive (MCF-7) and multidrug-resistant (MCF-7/Dx) human adenocarcinoma breast cancer cells. Assays for cell death, apoptosis, cell cycle progression and mitochondrial bioenergetic function were performed. Seven compounds (4b, 7b, 8b, 13b, 14b, 15b and 18b) showed greater antiproliferative activity against MCF-7/Dx cells than allicin. These compounds were also selective towards multidrug-resistant (MDR) cells, a consequence attributed to collateral sensitivity. Among them, 13b exhibited the greatest anticancer activity in both MCF-7/Dx and MCF-7 cells, with IC values of 18.54±0.24 and 46.50±1.98 μmol/L, respectively. 13b altered cellular morphology and arrested the cell cycle at the G/M phase. Additionally, 13b dose-dependently induced apoptosis, and inhibited cellular mitochondrial respiration in cells at rest and under stress. MDR presents a significant obstacle to the successful treatment of cancer clinically. These results demonstrate that thiosulfinate derivatives have potential as novel anticancer agents and may offer new therapeutic strategies for the treatment of chemoresistant cancers.
有机硫化合物源自葱属蔬菜，因其具有各种治疗作用而长期受到关注，包括抗癌活性。大蒜中的主要生物活性成分之一——蒜素，作为一种抗癌剂具有很大的应用前景；然而，其不稳定性使其不适合临床应用。本研究旨在研究体外稳定蒜素衍生物对人乳腺癌细胞的影响。在这项研究中，共合成了 22 种稳定的硫代亚磺酸酯衍生物，并对其体外对耐药（MCF-7/Dx）和多药耐药（MCF-7）人腺癌细胞的抗增殖活性进行了筛选。进行了细胞死亡、细胞凋亡、细胞周期进展和线粒体生物能学功能的测定。有 7 种化合物（4b、7b、8b、13b、14b、15b 和 18b）对 MCF-7/Dx 细胞的增殖抑制活性强于蒜素。这些化合物对多药耐药（MDR）细胞也具有选择性，这是由于协同敏感性所致。其中，化合物 13b 在 MCF-7/Dx 和 MCF-7 细胞中均表现出最强的抗癌活性，IC 值分别为 18.54±0.24 和 46.50±1.98 μmol/L。13b 改变了细胞形态，并将细胞周期阻滞在 G/M 期。此外，13b 剂量依赖性地诱导细胞凋亡，并抑制静止和应激状态下细胞的细胞线粒体呼吸。多药耐药性是癌症临床治疗成功的重大障碍。这些结果表明，硫代亚磺酸酯衍生物具有作为新型抗癌剂的潜力，可能为治疗耐药性癌症提供新的治疗策略。
