The Therapeutic Effects of Dihydroartemisinin on Cisplatin-Resistant Gastric Cancer Cells

Abstract

Background: Dihydroartemisinin (DHA) exhibited anti-tumor effect in a variety of cancer cells, but its mechanism of action is unclear. Objective: To investigate the therapeutic effects of DHA on Cisplatin (DDP)-resistant gastric cancer cell strain SGC7901/DDP and the possible molecular mechanism. Methods: Cells were treated with DHA in a dose- and time-dependent manner, after which their proliferation, apoptosis, invasion, and migration abilities were evaluated. We further evaluated autophagy with mRFP-GFP-LC3 adenovirus transfection and transmission electron microscopy and also detected the expression levels of proteins (related to autophagy and apoptosis) via western blot. Meanwhile, the influence of DHA on cisplatin resistance was detected through a sensitization test and the evaluation of P-gp expression levels. Results: DHA effectively inhibited the proliferation, invasion, and migration of SGC7901/DDP cells and induced cell apoptosis which was accompanied by caspase-8/9/3 activation. Furthermore, exposure to DHA resulted in a pronounced increase in autophagy proteins, including Beclin-1 and LC3 II with PI3K/AKT/mTOR pathway inhibition. Additionally, enhancement of cisplatin sensitivity occurred in SGC7901/DDP cells treated with DHA, which was accompanied by P-gp downregulation. Conclusion: DHA exerts an anti-cancer effect on SGC7901/DDP cells and the mechanisms possibly include enhancement of autophagy via PI3K/AKT/mTOR inhibition, inducement of apoptosis through caspase-dependent and mitochondrial pathway, and enhancement of cisplatin sensitivity through P-gp inhibition.