1.Withaferin-A-A Natural Anticancer Agent with Pleitropic Mechanisms of Action.
Lee IC1, Choi BY2. Int J Mol Sci. 2016 Mar 4;17(3). pii: E290. doi: 10.3390/ijms17030290.
Cancer, being the second leading cause of mortality, exists as a formidable health challenge. In spite of our enormous efforts, the emerging complexities in the molecular nature of disease progression limit the real success in finding an effective cancer cure. It is now conceivable that cancer is, in fact, a progressive illness, and the morbidity and mortality from cancer can be reduced by interfering with various oncogenic signaling pathways. A wide variety of structurally diverse classes of bioactive phytochemicals have been shown to exert anticancer effects in a large number of preclinical studies. Multiple lines of evidence suggest that withaferin-A can prevent the development of cancers of various histotypes. Accumulating data from different rodent models and cell culture experiments have revealed that withaferin-A suppresses experimentally induced carcinogenesis, largely by virtue of its potent anti-oxidative, anti-inflammatory, anti-proliferative and apoptosis-inducing properties.
2.Hepatoprotective effect of withanolide-rich fraction in acetaminophen-intoxicated rat: decisive role of TNF-α, IL-1β, COX-II and iNOS.
Devkar ST1, Kandhare AD2, Zanwar AA1, Jagtap SD3, Katyare SS1, Bodhankar SL2, Hegde MV1. Pharm Biol. 2016 Apr 4:1-10. [Epub ahead of print]
CONTEXT: Overdose of acetaminophen (APAP) is common in humans and is often associated with hepatic damage. Withania somnifera (L.) Dunal (Solanaceae) shows multiple pharmacological activities including antioxidant and anti-inflammatory potential.
3.Withaferin A induces heme oxygenase (HO-1) expression in endothelial cells via activation of the Keap1/Nrf2 pathway.
Heyninck K1, Sabbe L2, Chirumamilla CS3, Szarc Vel Szic K3, Vander Veken P4, Lemmens KJ5, Lahtela-Kakkonen M6, Naulaerts S7, Op de Beeck K8, Laukens K7, Van Camp G9, Weseler AR5, Bast A5, Haenen GR5, Haegeman G2, Vanden Berghe W10. Biochem Pharmacol. 2016 Apr 1. pii: S0006-2952(16)30022-3. doi: 10.1016/j.bcp.2016.03.026. [Epub ahead of print]
Withaferin A (WA), a natural phytochemical derived from the plant Withania somnifera, is a well-studied bioactive compound exerting a broad spectrum of health promoting effects. To gain better insight in the potential therapeutic capacity of WA, we evaluated the transcriptional effects of WA on primary human umbilical vein endothelial cells (HUVECs) and an endothelial cell line (EA.hy926). RNA microarray analysis of WA treated HUVEC cells demonstrated increased expression of the antioxidant gene heme oxygenase (HO-1). Transcriptional regulation of this gene is strongly dependent on the transcription factor NF-E2-related factor 2 (Nrf2), which senses chemical changes in the cell and coordinates transcriptional responses to maintain chemical homeostasis via expression of antioxidant genes and cytoprotective Phase II detoxifying enzymes. Under normal conditions, Nrf2 is kept in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), an adaptor protein controlling the half-life of Nrf2 via constant proteasomal degradation.
4.Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells.
Suman S1, Das TP1, Sirimulla S2, Alatassi H3, Ankem MK1, Damodaran C1. Oncotarget. 2016 Feb 12. doi: 10.18632/oncotarget.7351. [Epub ahead of print]
The oncogenic activation of AKT gene has emerged as a key determinant of the aggressiveness of colorectal cancer (CRC); hence, research has focused on targeting AKT signaling for the treatment of advanced stages of CRC. In this study, we explored the anti-tumorigenic effects of withaferin A (WA) on CRC cells overexpressing AKT in preclinical (in vitro and in vivo) models. Our results indicated that WA, a natural compound, resulted in significant inhibition of AKT activity and led to the inhibition of cell proliferation, migration and invasion by downregulating the epithelial to mesenchymal transition (EMT) markers in CRC cells overexpressing AKT. The oral administration of WA significantly suppressed AKT-induced aggressive tumor growth in a xenograft model. Molecular analysis revealed that the decreased expression of AKT and its downstream pro-survival signaling molecules may be responsible for tumor inhibition. Further, significant inhibition of some important EMT markers, i.