Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes
- Authors
- 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
- Issue Date
- Mar-2022
- Publisher
- MDPI
- Keywords
- 1,2,4-trioxanes; P-glycoprotein; anticancer; molecular docking; mechanism of action
- Citation
- PHARMACEUTICALS, v.15, no.3
- Journal Title
- PHARMACEUTICALS
- Volume
- 15
- Number
- 3
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/83965
- DOI
- 10.3390/ph15030360
- ISSN
- 1424-8247
- Abstract
- 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 7 and 8 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 7 and 8 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 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 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.
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