Dihydroartemisinin Inhibits Angiogenesis in Breast Cancer via Suppressing NF-κB/MMP-2/-9 Pathway

Abstract Purpose Dihydroartemisinin (DHA), a derivative of artemisinin that is well-known as an antimalarial drug, has been reported to have anti-tumor and anti-angiogenesis effects. However, whether and how it inhibits angiogenesis in breast cancer is poorly understood. In this study, we detected the anti-angiogenesis effect of DHA on breast cancer. Methods Firstly, we detect the anti-angiogenesis effect of DHA on breast cancer in a chick chorioallantois membrane model. Then, we collected the conditioned medium of MDA-MB-231cells used in aortic ring angiogenesis assay, and HUVECs migration and tube formation assay. Finally, we used gelatin zymography, cellular immunofluorescence assay and western blot analysis to study signaling modulators regulated by DHA in MDA-MB-231 cells. Results The results showed that angiogenesis induced by MDA-MB-231 cells was attenuated by DHA. Vessel sprout and tube-formation of vascular endothelial cells were also depressed when cultured with CM from MDA-MB-231 pretreated with DHA. What’s more, the expression, and activities of matrix metalloproteinase 2 and 9 (MMP-2/-9) in MDA-MB-231 cells were downregulated by DHA. Further studies showed that DHA downregulated the expression of p-PI3K, p-AKT, p-ERK, and p-NF-κB proteins in tumor cells. Conclusion DHA was highly efficacious in inhibiting angiogenesis induced by breast cancer cells. The downregulating of MMP-2/9 through inhibiting phosphorylation of PI3K, AKT, and ERK in tumor cells may be the key factors in the inhibitory effect of DHA on angiogenesis.