http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-1740.pdf

Cancer—an ayurvedic perspective

Ethnopharmacology and drug discovery.

Withaferin A (WA) is derived from the medicinal plant Withania somnifera , which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments. We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo . The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner. The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone–associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. The cytoplasmic histone–associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. injections of 4 mg WA/kg body weight. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice. These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human breast cancer cells. [Cancer Res 2008;68(18):7661–9]

https://cancerres.aacrjournals.org/content/canres/68/18/7661.full.pdf

Withaferin A Causes FOXO3a- and Bim-Dependent Apoptosis and Inhibits Growth of Human Breast Cancer Cells In vivo

Withaferin A (WA) is a steroidal lactone purified from medicinal plant “Indian Winter Cherry” that is widely researched for its variety of properties, including antitumor effects. However, the primary molecular target of WA is unknown. By chemical structure analysis, we hypothesized that Withaferin A might be a natural proteasome inhibitor. Computational modeling studies consistently predict that C1 and C24 of WA are highly susceptible toward a nucleophilic attack by the hydroxyl group of N-terminal threonine of the proteasomal chymotrypsin subunit β5. Furthermore, WA potently inhibits the chymotrypsin-like activity of a purified rabbit 20S proteasome (IC50 = 4.5 μM) and 26S proteasome in human prostate cancer cultures (at 5-10 μM) and xenografts (4-8 mg/kg/day). Inhibition of prostate tumor cellular proteasome activity in cultures and in vivo by WA results in accumulation of ubiquitinated proteins and three proteasome target proteins (Bax, p27, and IκB-α) accompanied by androgen receptor protein suppression (in androgen-dependent LNCaP cells) and apoptosis induction. Treatment of WA under conditions of the aromatic ketone reduction, or reduced form of Celastrol, had significantly decreased the proteasome-inhibitory and apoptosis-inducing activities. Treatment of human prostate PC-3 xenografts with WA for 24 days resulted in 70% inhibition of tumor growth in nude mice, associated with 56% inhibition of the tumor tissue proteasomal chymotrypsinlike activity. Our results demonstrate that the tumor proteasome β5 subunit is the primary target of WA, and inhibition of the proteasomal chymotrypsin-like activity by WA in vivo is responsible for, or contributes to, the antitumor effect of this ancient medicinal compound.

https://molpharm.aspetjournals.org/content/molpharm/early/2006/11/08/mol.106.030015.full.pdf

The tumor proteasome is a primary target for the natural anticancer compound withaferin A isolated from indian winter cherry

Withania somnifera, also called 'Indian ginseng', is an important medicinal plant of the Indian subcontinent. It is widely used, singly or in combination, with other herbs against many ailments in Indian Systems of Medicine since time immemorial. Withania somnifera contains a spectrum of diverse phytochemicals enabling it to have a broad range of biological implications. In preclinical studies, it has shown anti-microbial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective, and anti-diabetic properties. Additionally, it has demonstrated the ability to reduce reactive oxygen species, modulate mitochondrial function, regulate apoptosis, and reduce inflammation and enhance endothelial function. In view of these pharmacologic properties, W. somnifera is a potential drug candidate to treat various clinical conditions, particularly related to the nervous system. In this review, we summarize the pharmacologic characteristics and discuss the mechanisms of action and potential therapeutic applications of the plant and its active constituents.

Pharmacologic overview of Withania somnifera, the Indian Ginseng

Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extracts in experimental immune inflammation.

Column chromatographic fractionation of essential oil obtained by hydrodistillation from the flowering tops of S. ixiocephala resulted in the isolation of beta-caryophyllene, fenchyl acetate, T-cadinol and a new sesquiterpene alcohol for which a name ixiocephol has been proposed. The beta-caryophyllene and fenchyl acetate were identified by Co-TLC with authentic samples whereas T-cadinol and ixiocephol were structurally elucidated by UV, IR, 1H NMR, 13C NMR and Mass spectral data. The GC-MS analysis of the essential oil has also revealed the presence of various monoterpenoids and sesquiterpenoids. The essential oil of S. ixiocephala demonstrated a dose dependant anti-inflammatory activity in carrageenan-induced rat paw oedema. It has also revealed good activity in cotton pellet granuloma and adjuvant induced arthritis model in rats.

/pdf/phytochemical-investigation-and-evaluation-of-anti-3iqega0z5s.pdf

Ramesh Agarwal

Papers

Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extracts in experimental immune inflammation.

Phytochemical investigation and evaluation of anti-inflammatory and anti-arthritic activities of essential oil of Strobilanthus ixiocephala Benth.

Comparative phytochemical studies of Strobilanthus callosus and s. Ixiocephala roots