Dihydroartemisinin transiently activates the JNK/SAPK signaling pathway in endothelial cells

Abstract

Abstract. Artemisinin and its derivatives are well-known anti-malaria drugs and in the early stages of research for cancer treatment. Dihydroartemisinin (DHA), a more water-soluble derivative of artemisinin, has demonstrated strong anti-angiogenic activity. The purpose of the present study was to investigate the underlying molecular mechanisms of the effect of DHA on angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for apoptosis and activation of the c-Jun N-terminal kinase (JNK) signaling pathway, one of the major mitogen-activated protein kinase cascades. It was observed that 20 µM DHA induces transient activation of JNK in HUVECs. DHA also elevates the expression of cyclooxygenase-2 and matrix metalloproteinase-13, which is abolished by treatment with the JNK inhibitor SP600125. Although DHA persistently increases inhibitor of κB-α protein and thus inhibits nuclear factor-κB signaling, it does not affect apoptosis or caspase 3/9 activities in HUVECs. The present study provides key information for understanding the effects of DHA on endothelial cells, which is required for investigating its potential for clinic application as a chemotherapeutic agent.

Anti-angiogenic properties of artemisinin derivatives (Review)

“…As previously demonstrated, DHA, at a concentration of 20 µM, significantly increased the level of activated JNK in HUVECs at 6 h of incubation (44). In addition, the level of activated JNK plateaued at 12 h-incubation before starting to decline at 24 h (44).…”

“…DHA inhibits EC proliferation by reducing ERK1/2 expression and activation (1,11). In the meantime, ART and DHA appear to play distinct roles in JNK and p38 MAPK activation (3,11,44). In addition to decreasing VEGFR2 expression in ECs, artemisinins limit angiogenesis by mitigating the production of pro-angiogenic cytokines from tumor cells (2,21,52).…”

“…In addition, the level of activated JNK plateaued at 12 h-incubation before starting to decline at 24 h (44). Intriguingly, although the activation of JNK is also involved in apoptosis, DHA exerted no effect on HUVEC viability (44). Nonetheless, beginning from a concentration of 12.5 µM, ART decreased the level of activated JNK in HUVECs following incubation for 0.5 h (11) ( Fig.…”

Andrographolide inhibits proliferation and induces cell cycle arrest and apoptosis in human melanoma cells

“…Recent studies have suggested JNK signaling pathway plays important roles in many cellular events, such as regulating cell cycle, cell apoptosis and autophagy (19,20). To further elucidate the effect of Andro on JNK signal pathway, we measured the expression of JNK an p-P38 genes.…”

Dihydroartemisinin enhances VEGFR1 expression through up-regulation of ETS-1 transcription factor

“…Several signaling cascades including NF-κB, PKC, ERK, JNK, and p38 MAPK pathway have been reported to mediate the effects of DHA 38 - 42 . For example, DHA activates JNK signaling pathway and then increases the expression of cyclooxygenase-2 and matrix metalloproteinase-13 (MMP-13) 43 . Moreover, DHA plays a negative role in the expression of hypoxia inducible factor (HIF)-1α, angiogenic mediators VEGF, MMP9, MMP11, and collagens 30 , 44 .…”