title: Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells.
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.
authors: Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China; Department of Medical Oncology, Chenggong Hospital of Xiamen University, Xiamen, China.
authors: Yan-jun
authors: YJ
authors: Mi
authors: Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Guo-jun
authors: GJ
authors: Geng
authors: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
authors: Zheng-zhi
authors: ZZ
authors: Zou
authors: Department of Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Jing
authors: J
authors: Gao
authors: Department of Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Xian-yang
authors: XY
authors: Luo
authors: Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Yu
authors: Y
authors: Liu
authors: Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Ning
authors: N
authors: Li
authors: Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Chun-lei
authors: CL
authors: Li
authors: Department of Medical Oncology, Chenggong Hospital of Xiamen University, Xiamen, China.
authors: Yu-qiang
authors: YQ
authors: Chen
authors: Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Xiu-yi
authors: XY
authors: Yu
authors: Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors: Jie
authors: J
authors: Jiang
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D037621:Artemisinins; D051272:Glucose Transporter Type 1; C039060:artenimol; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D058570:TOR Serine-Threonine Kinases; D053181:Caspase 8; D005947:Glucose