Abstract
The medicinal plant Withania somnifera is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In Ayurveda, the major Traditional Indian medicine system, extracts from W. somnifera are distinctively employed for the treatment of arthritis and menstrual disorders. Because these conditions involve angiogenic processes we hypothesized that the W. somnifera extracts might contain angiogenesis inhibitors. We employed an endothelial cell-sprouting assay to monitor the purification of substances from W. somnifera root extracts and isolated as the active principle the previously known natural product withaferin A. We show that withaferin A inhibits human umbilical vein endothelial cell (HUVEC) sprouting in three-dimensional collagen-I matrix at doses which are relevant to NF-kappa B-inhibitory activity. Withaferin A inhibits cell proliferation in HUVECs (IC 50=12 nM) at doses that are significantly lower than those required for tumor cell lines through a process associated with inhibition of cyclin D1 expression. We propose that the inhibition of NF-kappa B by withaferin A in HUVECs occurs by interference with the ubiquitin-mediated proteasome pathway as suggested by the increased levels of poly-ubiquitinated proteins. Finally, withaferin A is shown to exert potent anti-angiogenic activity in vivo at doses that are 500-fold lower than those previously reported to exert anti-tumor activity in vivo. In conclusion, our findings identify a novel mode of action of withaferin A, which highlights the potential use of this natural product for cancer treatment or prevention.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 115-122 |
| Number of pages | 8 |
| Journal | Angiogenesis |
| Volume | 7 |
| Issue number | 2 |
| DOIs | |
| State | Published - Nov 24 2004 |
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Keywords
- angiogenesis inhibitor
- endothelial cell
- natural product
- NF-kappa B
- withaferin A
ASJC Scopus subject areas
- Cancer Research
- Pathology and Forensic Medicine
- Clinical Biochemistry
- Polymers and Plastics
Cite this
Withaferin A is a potent inhibitor of angiogenesis. / Mohan, Royce; Hammers, Hans; Bargagna-Mohan, Paola; Zhan, Xiaoguo; Herbstritt, Christopher; Ruiz, Antonio; Zhang, Li; Hanson, Art; Conner, Barry; Rougas, John; Pribluda, Victor.
In: Angiogenesis, Vol. 7, No. 2, 24.11.2004, p. 115-122.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Withaferin A is a potent inhibitor of angiogenesis
AU - Mohan, Royce
AU - Hammers, Hans
AU - Bargagna-Mohan, Paola
AU - Zhan, Xiaoguo
AU - Herbstritt, Christopher
AU - Ruiz, Antonio
AU - Zhang, Li
AU - Hanson, Art
AU - Conner, Barry
AU - Rougas, John
AU - Pribluda, Victor
PY - 2004/11/24
Y1 - 2004/11/24
N2 - The medicinal plant Withania somnifera is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In Ayurveda, the major Traditional Indian medicine system, extracts from W. somnifera are distinctively employed for the treatment of arthritis and menstrual disorders. Because these conditions involve angiogenic processes we hypothesized that the W. somnifera extracts might contain angiogenesis inhibitors. We employed an endothelial cell-sprouting assay to monitor the purification of substances from W. somnifera root extracts and isolated as the active principle the previously known natural product withaferin A. We show that withaferin A inhibits human umbilical vein endothelial cell (HUVEC) sprouting in three-dimensional collagen-I matrix at doses which are relevant to NF-kappa B-inhibitory activity. Withaferin A inhibits cell proliferation in HUVECs (IC 50=12 nM) at doses that are significantly lower than those required for tumor cell lines through a process associated with inhibition of cyclin D1 expression. We propose that the inhibition of NF-kappa B by withaferin A in HUVECs occurs by interference with the ubiquitin-mediated proteasome pathway as suggested by the increased levels of poly-ubiquitinated proteins. Finally, withaferin A is shown to exert potent anti-angiogenic activity in vivo at doses that are 500-fold lower than those previously reported to exert anti-tumor activity in vivo. In conclusion, our findings identify a novel mode of action of withaferin A, which highlights the potential use of this natural product for cancer treatment or prevention.
AB - The medicinal plant Withania somnifera is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In Ayurveda, the major Traditional Indian medicine system, extracts from W. somnifera are distinctively employed for the treatment of arthritis and menstrual disorders. Because these conditions involve angiogenic processes we hypothesized that the W. somnifera extracts might contain angiogenesis inhibitors. We employed an endothelial cell-sprouting assay to monitor the purification of substances from W. somnifera root extracts and isolated as the active principle the previously known natural product withaferin A. We show that withaferin A inhibits human umbilical vein endothelial cell (HUVEC) sprouting in three-dimensional collagen-I matrix at doses which are relevant to NF-kappa B-inhibitory activity. Withaferin A inhibits cell proliferation in HUVECs (IC 50=12 nM) at doses that are significantly lower than those required for tumor cell lines through a process associated with inhibition of cyclin D1 expression. We propose that the inhibition of NF-kappa B by withaferin A in HUVECs occurs by interference with the ubiquitin-mediated proteasome pathway as suggested by the increased levels of poly-ubiquitinated proteins. Finally, withaferin A is shown to exert potent anti-angiogenic activity in vivo at doses that are 500-fold lower than those previously reported to exert anti-tumor activity in vivo. In conclusion, our findings identify a novel mode of action of withaferin A, which highlights the potential use of this natural product for cancer treatment or prevention.
KW - angiogenesis inhibitor
KW - endothelial cell
KW - natural product
KW - NF-kappa B
KW - withaferin A
UR - http://www.scopus.com/inward/record.url?scp=20844449388&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20844449388&partnerID=8YFLogxK
U2 - 10.1007/s10456-004-1026-3
DO - 10.1007/s10456-004-1026-3
M3 - Article
C2 - 15516832
AN - SCOPUS:20844449388
VL - 7
SP - 115
EP - 122
JO - Angiogenesis
JF - Angiogenesis
SN - 0969-6970
IS - 2
ER -