Withaferin A from withania somnifera herb

Withaferin A is a withanolide chemical constituent from ashwagandha herb. It has been reported for its tumor cell growth inhibitory activity, antitumor effects, and impairing metastasis and angiogenesis.

Anti-inflammatory
Inhibition of monosodium urate crystal-induced inflammation by withaferin A.
J Pharm Pharm Sci. 2008; Sabina EP, Chandal S. School of Biotechnology, Chemical and Biomedical engineering, VIT University Vellore, Tamil Nadu, India.
Gouty arthritis is a characteristically intense acute inflammatory reaction resulting from the formation of sodium urate crystals in the joint cavity. In the present study, the effect of withaferin A, a steroidal lactone was investigated on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, indomethacin. The present findings clearly indicated that withaferin A exerted a strong anti-inflammatory effect against gouty arthritis.

Colon cancer
Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis.
Mol Cancer Ther. 2010: Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C. Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.
Notch signaling plays a crucial role in the development of colon cancer; targeting the Notch pathway may sensitize colon cancers to various adjuvant agents. The focus of our current study is to identify natural compounds that target Notch signaling and that might be beneficial for the prevention and treatment of colon cancer. Withaferin-A (WA) is a bioactive compound derived from Withania somnifera, which inhibits Notch-1 signaling and downregulates prosurvival pathways, such as Akt/NF-kappaB/Bcl-2, in three colon cancer cell lines (HCT-116, SW-480, and SW-620). In addition, WA downregulated the expression of mammalian target of rapamycin signaling components, pS6K and p4E-BP1, and activated c-Jun-NH(2)-kinase-mediated apoptosis in colon cancer cells. We also established the molecular link between Notch/Akt/mammalian target of rapamycin signaling by complementary approaches (i.e., overexpression of Notch-1 or inhibition of Notch-1 by small interfering RNA). Our results suggest that WA inhibits Notch-mediated prosurvival signaling, which facilitates c-Jun-NH(2)-kinase-mediated apoptosis in colon cancer cell lines. These results underscore the anticancer activity of WA, which exhibits potential for further development for targeted chemotherapy and/or chemoprevention strategies in the context of colon cancer.

Leukemia
Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation.
Apoptosis. 2008; Department of Immunology, School of Medicine, Keimyung University, Taegu, South Korea.
The mechanism by which withaferin A initiates apoptosis remains poorly understood. In the present report, we investigated the effect of withaferin A on the apoptotic pathway in U937 human promonocytic cells. We show that withaferin A induces apoptosis in association with the activation of caspase-3. JNK and Akt signal pathways play crucial roles in withaferin A-induced apoptosis in U937 cells. Furthermore, we have shown that overexpression of Bcl-2 and active Akt (myr-Akt) in U937 cells inhibited the induction of apoptosis, activation of caspase-3, and PLC-gamma1 cleavage by withaferin A. Taken together, our results indicated that the JNK and Akt pathways and inhibition of NF-kappaB activity were key regulators of apoptosis in response to withaferin A in human leukemia U937 cells.