Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect.
OBJECTIVE
This study examined the in vitro and in vivo angiogenic effects of norcantharidin (NCTD), a synthetic, small-molecule antitumor compound.


METHODS
Syngeneic colorectal adenocarcinoma CT26 cells were implanted in mice to examine the effect of NCTD on VEGF production and renal and hepatic toxicity. Human umbilical endothelial cells (HUVECs) were used to examine the in vitro effect of NCTD on viability, chemotaxis, vascular network tube formation, adhesive ability, anoikis, and mitogen-activated protein kinase (MAPK) signaling. A protein array was used for analysis of angiogenic factors released from NCTD-treated HUVECs.


RESULTS
NCTD suppressed plasma VEGF levels of tumor-bearing mice, without renal or hepatic toxicity. In vitro, NCTD inhibited viability of normal HUVECs to a lesser extent than CT26 cancer cells. At concentrations less than those inhibiting 50% of the cells, NCTD inhibited migration and capillary-like tube formation of HUVECs. The anti-angiogenic effect of NCTD was accompanied by anoikis, down-regulation of integrin beta1, and breakdown of vimentin. NCTD decreased MAPK expression of phosphorylated (p)-JNK and p-ERK. P-P38 expression or P38 inhibitor SB203580 did not impair the effect of NCTD on viability or adhesion of HUVECs. In addition, NCTD inhibited the release of pro-angiogenic factors from HUVECs, but not from CT26 cells.


CONCLUSIONS
NCTD is a synthetic, small-molecule compound possessing anti-angiogenetic activity with potential use in anti-cancer therapy as an anti-metastatic and anti-angiogenic agent.
Chen
Yu-Jen
YJ
Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
Tsai
Yin-Meng
YM
Kuo
Cheng-Deng
CD
Ku
Kuo-Lung
KL
Shie
Huei-Sian
HS
Liao
Hui-Fen
HF
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D023102:Anoikis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D042461:Vascular Endothelial Growth Factor A; C069741:norcantharidin; D020928:Mitogen-Activated Protein Kinases