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

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 RPM18226 cells pretreated with 3 mu mol/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 mu mol/l dihydroartemisinin could significantly decrease vascular endothelial growth factor secretion by RPM18226 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 RPM18226 cells in hypoxia. In addition, we demonstrated that dihydroartemisinin reduced extracellular signal-regulated kinase 1/2 activation and inhibited growth of RPM18226 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.