The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1α in human rheumatoid arthritis fibroblast-like synoviocyte

Abstract

Increasing evidence indicates that the anti-malarial agent artemisinin and its derivatives may exert anti-angiogenic effect. In the present study, we explored the effect of artesunate, a artemisinin derivative, on TNFα- and hypoxia-induced expression of hypoxia inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) and inteleukin-8 (IL-8) in human rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), and further investigated the signal mechanism by which this compound modulates HIF-1α, VEGF and IL-8 expression. RA FLS obtained from patients with active rheumatoid arthritis were pretreated with artesunate, and then stimulated with TNFα and hypoxia. Production of VEGF and IL-8 was measured by ELISA. Nuclear location of HIF-1α was measured by confocal fluorescence microscopy. HIF-1α and other signal transduction proteins expression was measured by Western blot. Artesunate decreased the secretion of VEGF and IL-8 from TNFα- or hypoxia-stimulated RA FLS in a dose-dependent manner. Artesunate also inhibited TNFα- or hypoxia-induced nuclear expression and translocation of HIF-1α. We also showed that artesunate prevented Akt phosphorylation, but did not find evidence that phosphorylation of p38 and ERK was affected. TNFα- or hypoxia-induced secretion of VEGF and IL-8 and expression of HIF-1α were hampered by treatment with the PI3 kinase inhibitor LY294002, suggesting that inhibition of PI3 kinase/Akt activation might inhibit VEGF and IL-8 secretion and HIF-1α expression induced by TNFα or hypoxia. Our results suggest that artesunate inhibits angiogenic factor expression in RA FLS, and provide novel evidence that, as a low-cost agent, artesunate may have therapeutic potential for RA.

Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish

“…Studies with in vitro cell models, such as endothelial cells, and ex vivo models, such as the microvessel-like formation assay, indicate that DHA, along with other derivatives, can downregulate VEGF expression and inhibit angiogenesis [24,[26][27][28] . Moreover, the cytotoxicity of DHA might play a role in its anti-angiogenic function in ex vivo models inhibiting the proliferation of vessels in the medium by killing single cells.…”

Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes

“…1b, tumor pictures). In other xenograft models, the antiangiogenic effect of artemisinin has been attributed to the inhibition of epidermal growth factor and vascular endothelia growth factor receptor expressions [32,33].…”

Dihydroartemisinin inhibits endothelial cell proliferation through the suppression of the ERK signaling pathway

“…DHA alters the expression of a variety of genes in the vascular system. In particular, DHA downregulates the transcription of key components of the VEGF/VEGFR2 axis, which promotes angiogenesis (32,33). In addition to inhibiting the activation of the ERK signaling, the present data suggest that downregulation of the ERK1/2 gene expression may also contribute to the anti-angiogenesis effects of DHA.…”