The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-kappaB pathway.
Several natural compounds, especially plant products and dietary constituents, are able to exhibit 'angiopreventive' (anti-angiogenic chemoprevention) activities both in vitro and in vivo. Deguelin is a rotenoid of the flavonoid family with chemopreventive activities able to decrease tumor incidence in animal models for lung, colon, mammary and skin carcinogenesis through Akt inhibition. Here we show that deguelin belongs to the 'angiopreventive' molecules and provide evidence for molecular events associated with its anti-angiogenic properties. The data show that deguelin inhibits HUVE cells growth by inducing cell-cycle arrest in the G0/G1 phase and in the absence of apoptosis. Growth arrest is associated with induction of p21 and p53 and decreased survivin levels. Deguelin also interferes with several points in the angiogenic process, including inhibition of endothelial cell migration, invasion and metalloprotease production, and potently inhibits in vivo angiogenesis and vascular tumor growth. In addition to Akt, the nuclear factor-kappaB (NF-kappaB) kinase pathway, which plays a critical role in the regulation of inflammation, vascular homeostasis and angiogenesis, was also repressed by deguelin even in the presence of inflammatory stimuli such as tumor necrosis factor-alpha (TNF-alpha). These findings reveal a new therapeutic potential for deguelin in angioprevention and anti-angiogenic therapy.
Dell'Eva
Raffaella
R
Molecular Oncology Laboratory, National Institute for Cancer Research Largo R. Benzi 10, Italy.
Ambrosini
Claudia
C
Minghelli
Simona
S
Noonan
Douglas M
DM
Albini
Adriana
A
Ferrari
Nicoletta
N
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006706:Homeostasis; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D020533:Angiogenesis Inhibitors; D017931:DNA Primers; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D012402:Rotenone; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); C107676:deguelin