title: Dihydroartemisinin inhibits angiogenesis induced by multiple myeloma RPMI8226 cells under hypoxic conditions via downregulation of vascular endothelial growth factor expression and suppression of vascular endothelial growth factor secretion.
abstract: Multiple myeloma remains incurable to date; therefore, new biologically target-based therapies are urgently needed. Our previous studies have showed that the antimalarial dihydroartemisinin possessed antiangiogenic activity in solid tumors. The present study evaluated the effect of dihydroartemisinin on human multiple myeloma-induced angiogenesis under hypoxia and elucidated its mechanism of action. An in-vivo chicken chorioallantoic membrane model was used to examine the effect of dihydroartemisinin on multiple myeloma-induced angiogenesis. Compared with conditioned medium of control, conditioned medium from human multiple myeloma RPMI8226 cells pretreated with 3 micromol/l dihydroartemisinin in hypoxia was observed to reduce microvessel growth on chicken chorioallantoic membranes by approximately 28.6% (P<0.05). The level of vascular endothelial growth factor in conditioned medium was determined by enzyme-linked immunosorbent assay. The results confirmed that 3 micromol/l dihydroartemisinin could significantly decrease vascular endothelial growth factor secretion by RPMI8226 cells (P<0.05), which correlated well with the reduction of multiple myeloma-induced angiogenesis on chicken chorioallantoic membranes. Western blot and reverse transcription-polymerase chain reaction results revealed that dihydroartemisinin downregulated the expression of vascular endothelial growth factor in RPMI8226 cells in hypoxia. In addition, we demonstrated that dihydroartemisinin reduced extracellular signal-regulated kinase 1/2 activation and inhibited growth of RPMI8226 cells under hypoxic conditions. Therefore, we concluded that dihydroartemisinin, which is already used to treat malaria and is well tolerated, possesses potential as an antiangiogenic drug in multiple myeloma therapy and thereby may improve patient outcome.
authors.affiliation: Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PRC.
authors.forename: Xiu-Hua
authors.initials: XH
authors.lastname: Wu
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Lee
mesh_terms: D000481:Allantoin / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D037621:Artemisinins / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D017077:Culture Media, Conditioned; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D000860:Hypoxia; D008566:Membranes / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
chemical_list: D020533:Angiogenesis Inhibitors; D037621:Artemisinins; D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D000481:Allantoin; C039060:artenimol; D048049:Extracellular Signal-Regulated MAP Kinases; C022616:thiazolyl blue