Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-κB pathway
Dihydroartemisinin (DHA) has recently shown antitumor activity in human pancreatic cancer cells. However, its effect on antiangiogenic activity in pancreatic cancer is unknown, and the mechanism is unclear. This study was aimed to investigate whether DHA would inhibit angiogenesis in human pancreatic cancer.
Cell viability and proliferation, tube formation of human umbilical vein endothelial cells (HUVECs), nuclear factor (NF)-κB DNA-binding activity, expressions of vascular endothelial growth factor (VEGF), interleukin (IL)-8, cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9 were examined in vitro. The effect of DHA on antiangiogenic activity in pancreatic cancer was also assessed using BxPC-3 xenografts subcutaneously established in BALB/c nude mice.
DHA inhibited cell proliferation and tube formation of HUVECs in a time- and dose-dependent manner and also reduced cell viability in pancreatic cancer cells. DHA significantly inhibited NF-κB DNA-binding activity, so as to tremendously decrease the expression of NF-κB-targeted proangiogenic gene products: VEGF, IL-8, COX-2, and MMP-9 in vitro. In vivo studies, DHA remarkably reduced tumor volume, decreased microvessel density, and down-regulated the expression of NF-κB-related proangiogenic gene products.
Inhibition of NF-κB activation is one of the mechanisms that DHA inhibits angiogenesis in human pancreatic cancer. We also suggest that DHA could be developed as a novel agent against pancreatic cancer.
KeywordsPancreatic cancer Dihydroartemisinin Antiangiogenesis Nuclear factor-κB
This work was supported in part by grants from the New Century Support Foundation for Elitist of Chinese Ministry of Education (NCET-07-0248), the Scientific Foundation for Prominent Youth of Heilongjiang Province, China (JC200717), the Scientific and Technological Project of Heilongjiang Province, China (GC09C407-2), and the National Natural Scientific Foundation of China (30571808, 30872987). The authors would like to extend their gratefulness to Ming Mu for her technical assistance.
Conflict of interest
No conflict of interest.
- 2.Liu MP, Ma JY, Pa BR, Ma LS (2001) The study of pancreatic cancer in China. World Chin J Digestol 9:1103–1109Google Scholar
- 29.Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K (1999) Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 5:7234–7243Google Scholar
- 32.Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ (2000) Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60:5334–5339PubMedGoogle Scholar