Abstract
Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA-suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2-Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells.
Highlights
Lung cancer is the most common malignant tumor and the leading cause of cancer-related mortality worldwide
To determine the effects of DHA on human Non-small cell lung cancer (NSCLC) cell viability, A549 and PC-9 cells were exposed to different concentrations of DHA for up to 24 h and 48 h, followed by the determination of cell viability using MTT assay
To determine if the cytotoxic effect of DHA was due to induction of apoptosis, A549 and PC-9 cells were treated with different concentration of DHA for 24 h and 48 h and cell apoptosis was determined by Annexin V-FITC and propidium iodide (PI) staining and flow cytometry analysis
Summary
Lung cancer is the most common malignant tumor and the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Resistance of NSCLC cells to apoptosis is a major obstacle in anticancer treatment. Current researches focus on the development of innovative compounds that promote the apoptosis of therapy-resistant NSCLC cells. DHA has been shown to exert anticancer effects by induction of apoptosis without obvious side effects in lung carcinomas [5]. Ionizing radiation potentiates DHA-induced NSCLC cells apoptosis [6]. Apart from its prominent pro-apoptotic effect, DHA affects cancer cell functions, including tumor cell proliferation [7], angiogenesis [8], and immune regulation [9]. The exact molecular mechanisms of DHA anticancer effects remain to be fully investigated
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