alpha-Chaconine inhibits angiogenesis in vitro by reducing matrix metalloproteinase-2.
alpha-Chaconine, a naturally occurring steroidal glycoalkaloid in potato sprouts, was found to possess anti-carcinogenic properties, such as inhibiting proliferation, migration, invasion, and inducing apoptosis of tumor cells. However, the effect of alpha-chaconine on tumor angiogenesis remains unclear. In the present study, we examined the effect of alpha-chaconine on angiogenesis in vitro. Data demonstrated that alpha-chaconine inhibited proliferation of bovine aortic endothelial cells (BAECs) in a dose-dependent manner. When treated with non-toxic doses of alpha-chaconine, cell migration, invasion and tube formation were markedly suppressed. Furthermore, alpha-chaconine reduced the expression and activity of matrix metalloproteinase-2 (MMP-2), which is involved in angiogenesis. Our biochemical assays indicated that alpha-chaconine potently suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), phosphatidylinositide-3 kinase (PI3K) and Akt, while it did not affect phosphorylation of extracellular signal regulating kinase (ERK) and p38. In addition, alpha-chaconine significantly increased the cytoplasmic level of inhibitors of kappaBalpha (IkappaBalpha) and decreased the nuclear level of nuclear factor kappa B (NF-kappaB), suggesting that alpha-chaconine could inhibit NF-kappaB activity. Furthermore, the treatment of inhibitors specific for JNK (SP600125), PI3K (LY294002) or NF-kappaB (pyrrolidine dithiocarbamate) to BAECs reduced tube formation. Taken together, the results suggested that alpha-chaconine inhibited migration, invasion and tube formation of BAECs by reducing MMP-2 activities, as well as JNK and PI3K/Akt signaling pathways and inhibition of NF-kappaB activity. These findings reveal a new therapeutic potential for alpha-chaconine on anti-angiogenic therapy.
Lu
Ming-Kun
MK
Department of Psychiatry, Chi-Mei Medical Center, Taiwan.
Chen
Pei-Hsieng
PH
Shih
Yuan-Wei
YW
Chang
Ya-Ting
YT
Huang
En-Tze
ET
Liu
Cheng-Ruei
CR
Chen
Pin-Shern
PS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D036226:Seedlings; D012992:Solanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011198:Solanum tuberosum / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D016328:NF-kappa B; D010936:Plant Extracts; D012992:Solanine; C011860:alpha-chaconine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2