Withaferin A

Withaferin A is a steroidal lactone, derived from Acnistus arborescens, Withania somnifera (Indian Winter cherry or Ashwagandha in Sanskrit) and other members of Solanaceae family. It has been traditionally used in ayurvedic medicine. It is the first member of the withanolide class of ergostane type product to be discovered. This natural product has wide range of pharmacological activities including cardioprotective, anti-inflammatory, immuno-modulatory, anti-angiogenesis, anti-metastasis and anti-carcinogenic properties.Withanolides are a group of naturally occurring C28- steroidal lactones. They contain four cycloalkane ring structures, three cyclohexane rings and one cyclopentane ring. Withaferin A is highly reactive because of the ketone-containing unsaturated A ring, the epoxide in the B ring, and the unsaturated lactone ring. The double bond in ring A and the epoxide ring are mainly responsible for the cytotoxicity. The 22nd and 26th carbons of the ergostane skeleton in withaferin A and related steroidal compounds are oxidized to form a six-membered delta lactone unit. NMR spectral analysis identifies C3 in the unsaturated A ring as the main nucleophilic target site for ethyl mercaptan, thiophenol and L-cysteine ethyl ester in vitro. A library of 2, 3-dihydro-3β-substituted derivatives are synthesized by regio/stereoselective Michael addition to ring A. These analogs are being tested for its activity in neuro-degenerative diseases, autoimmune and inflammatory diseases and in cancer.3-azido withaferin A (3-azidoWA), a stable derivative of withaferin A, has been shown to inhibit cancer cell motility and invasion in wound healing by selectively suppressing MMP-2 activity in human cervical and prostate cell lines. It enhances the secretion of Par-4 which in turn suppresses MMP-2 expression and activity that is required for tumor metastasis. 3-azidoWA acts as a tumor suppressor by inducing Par-4, TIMP-1 and by reducing the levels of pAkt and pERK that are activated in various cancers. This finding has augmented the therapeutic potential of the pro-apoptotic protein Par-4 in cancer. Researchers have shown that 3-azidoWA abrogated neovascularisation in vivo in a dose-dependent manner.Withania extracts suppresses the production of various pro-inflammatory molecules in many in vitro models. Anti-inflammatory property of withaferin A has been attributed to its ability to suppress alpha-2 macroglobulin, NF-κB and AP1. Several withanolides selective inhibition of enzyme cyclooxygenase-2 (COX-2) that increases during inflammation.Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which inactivate the tumor suppressor protein p53 and pRb respectively. Withaferin A was found to down regulate expression of E6 and E7 oncoproteins, induce accumulation of p53, causes G2/M cell cycle arrest, alters the expression levels of apoptotic markers Bcl2, Bax and caspase3. In athymic mice model, withaferin reduced 70% of the tumor volume. Therefore, withaferin A can be a potential therapeutic agent for the treatment of cervical cancer without major side effects. Withaferin A has been shown to enhance radiation-induced apoptosis in certain cell lines. However, its mechanism of action on cell death is not well understood. It has been suggested that sensitization of cancer cells to radiation is due to the inhibition of NF-κB. It exhibits anti-tumor as well as anti-inflammatory activities. It can act as an immuno-suppressant by inhibiting NF-κB activation. In animal models, it prevented skin cancer induced by ultraviolet radiation. The antioxidant property of withaferin aid in the prevention of DNA damage by mutagens; in combination with detoxifying, anti-inflammatory and immunomodulatory effects, it can contribute to the chemopreventive action.In the withania somnifera plant, the withanolide, Withaferin A, is present in the leaves. Withanolides are terpenoids, which are synthesized in plants using isoprenoids as precursors. Isoprenoids can be synthesized through mevalonate (MVA) or 1-deoxy-D-xylulose 5-phosphate (DOXP) pathways. Isoprenogenesis significantly governs withanolide synthesis.Par-4