title: Dihydroartemisinin inhibits endothelial cell proliferation through the suppression of the ERK signaling pathway.
abstract: Disrupting tumor angiogenesis serves as an important strategy for cancer therapy. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has exhibited potent anti-angiogenic activity. However, the molecular mechanisms underlying this effect have not been fully understood. The present study aimed to investigate the role of DHA on endothelial cell proliferation, the essential process in angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for proliferation, apoptosis and activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Proliferation of HUVECs was inhibited by 20 µM DHA without induction of apoptosis. DHA also reduced the phosphorylation of ERK1/2, and downregulated the mRNA and protein expression of ERK1/2 in HUVECs. In addition, DHA suppressed the transcription and protein expression of ERK1/2 downstream effectors c-Fos and c-Myc. Electrical cell-substrate impedance sensing real-time analysis demonstrated that ERK signaling inhibitor PD98059 comprises the anti-proliferative effects of DHA. Thus, DHA inhibits endothelial cell proliferation by suppressing the ERK signaling pathway. The present study strengthened the potential of DHA as an angiogenesis inhibitor for cancer treatment.
authors.affiliation: Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Suhua
authors.initials: S
authors.lastname: Yan
authors.affiliation: Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Traditional Chinese Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medicine, Hospital of Shandong Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
mesh_terms: D037621:Artemisinins / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D037621:Artemisinins; C039060:artenimol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3