Ng Jerome P L, Tiwari Mohit K, Nasim Ali Adnan, Zhang Rui Long, Qu Yuanqing, Sharma Richa, Law Betty Yuen Kwan, Yadav Dharmendra K, Chaudhary Sandeep, Coghi Paolo, Wong Vincent Kam Wai
Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India.
Pharmaceuticals (Basel). 2022 Mar 16;15(3):360. doi: 10.3390/ph15030360.
1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only and showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds and exhibited docking scores of -7.089 and -8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides and showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides and were also found to decrease cell membrane potential. In addition, peroxides and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.
1,2,4-三氧杂环己烷是一种药效基团，具有广泛的生物活性，包括抗癌作用。在本研究中，研究了一组10种选定过氧化物对五种表型不同的癌细胞系（A549、A2780、HCT8、MCF7和SGC7901）及其相应的耐药癌细胞系的细胞毒性作用和抗癌作用机制。在所有过氧化物中，只有[具体过氧化物1]和[具体过氧化物2]在100 nM浓度下表现出更好的P-糖蛋白（P-gp）抑制作用。这些体外结果通过计算机对接和分子动力学（MD）研究进一步得到验证，其中化合物[具体过氧化物1]和[具体过氧化物2]的对接分数分别为-7.089和-8.196 kcal/mol，并且在MD模拟的100 ns期间总体保持稳定。进一步的实验表明，过氧化物[具体过氧化物1]和[具体过氧化物2]对A549细胞中的活性氧（ROS）积累和半胱天冬酶-3活性没有显著影响。还发现过氧化物[具体过氧化物1]和[具体过氧化物2]会降低细胞膜电位。此外，过氧化物[具体过氧化物1]和8被证明可氧化黄素辅因子，这可能阐明了其作用机制。总之，1,2,4-三氧杂环己烷诱导的细胞凋亡通过细胞膜电位超极化的ROS和半胱天冬酶-3非依赖性途径进行。
