Journal Article

Dihydroartemisinin Inhibits Glucose Uptake and Cooperates with Glycolysis Inhibitor to Induce Apoptosis in Non-Small Cell Lung Carcinoma Cells

Zou, Zheng-zhi, Li, Ning, Liu, Yu, Luo, Xian-yang, Geng, Guo-jun, Chen, Yu-qiang, Mi, Yan-jun, Gao, Jing, Li, Chun-lei, Yu, Xiu-yi, Jiang, Jie

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Adenosine Triphosphate - biosynthesis / Apoptosis / Apoptosis - drug effects / Apoptosis-inducing factor / Artemisinins - antagonists & inhibitors / Artemisinins - pharmacology / Autophagy / Biological Transport - drug effects / Breast cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - pathology / Caspase / Caspase 8 - metabolism / Caspase-9 / Cell growth / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Survival - drug effects / Chemotherapy / Colorectal cancer / Cytochrome / Cytochrome c / Cytoplasm / Cytotoxicity / Deoxyglucose - pharmacology / Dihydroartemisinin / Drug Synergism / Gene Expression Regulation, Neoplastic - drug effects / Glucose / Glucose - metabolism / Glucose - pharmacology / Glucose Transporter Type 1 - metabolism / Glycolysis / Glycolysis - drug effects / Herbal medicine / Humans / Inhibition / Inhibitors / Ionizing radiation / Lactates / Lactic acid / Life sciences / Lung cancer / Lung carcinoma / Lung diseases / Lung Neoplasms - pathology / Metabolism / Non-small cell lung cancer / Non-small cell lung carcinoma / Ovarian cancer / Oxygen / Rapamycin / Reactive oxygen species / Signal Transduction - drug effects / Small cell lung carcinoma / Substance abuse treatment / Surgery / Thoracic surgery / TOR protein / TOR Serine-Threonine Kinases - metabolism / Toxicity / Tumors