Selective Killing of Cancer Cells by Leaf Extract of Ashwagandha: Identification of a Tumor-Inhibitory Factor and the First Molecular Insights to Its Effect
ABSTRACT Ashwagandha is regarded as a wonder shrub of India and is commonly used in Ayurvedic medicine and health tonics that claim its variety of health-promoting effects. Surprisingly, these claims are not well supported by adequate studies, and the molecular mechanisms of its action remain largely unexplored to date. We undertook a study to identify and characterize the antitumor activity of the leaf extract of ashwagandha.
Selective tumor-inhibitory activity of the leaf extract (i-Extract) was identified by in vivo tumor formation assays in nude mice and by in vitro growth assays of normal and human transformed cells. To investigate the cellular targets of i-Extract, we adopted a gene silencing approach using a selected small hairpin RNA library and found that p53 is required for the killing activity of i-Extract.
By molecular analysis of p53 function in normal and a variety of tumor cells, we found that it is selectively activated in tumor cells, causing either their growth arrest or apoptosis. By fractionation, purification, and structural analysis of the i-Extract constituents, we have identified its p53-activating tumor-inhibiting factor as with a none.
We provide the first molecular evidence that the leaf extract of ashwagandha selectively kills tumor cells and, thus, is a natural source for safe anticancer medicine.
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- "Ferlay et al. (2000) reported that worldwide more than 5 million people are diagnosed with cancer and more than 3.5 million people die from cancer each year. Managing human malignancies still constitutes a major challenge for contemporary medicine (Coufal et al., 2007 and Widodo et al., 2007). Although with progress in understanding cancer biology, many new antineoplastic therapies have been developed that rely primarily on surgery, chemotherapy, radiotherapy, hormone therapy, and immunotherapeutic approaches (Khorshid et al., 2010). "
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- "The present computational analysis demonstrated such model and endorsed the activation of p53 function as a mechanism of death in human cancer cells. Similar to MKT-077, withanone caused selective killing of cancer cells, leaving normal human cells unharmed (Widodo et al., 2007). Our computational analysis showed, for the first time, that withanone could bind to mortalin in the region that contained p53 and MKT-077 binding sites and hence could release p53 from mortalin–p53 complex. "
ABSTRACT: Mortalin binds to p53 tumor suppressor protein and sequesters it in the cytoplasm. This results in an inhibition of the transcriptional activation and control of centrosome duplication functions of p53, thus contributing to human carcinogenesis. Abrogation of mortalin-p53 interaction and reactivation of p53 function could be a valid proposition for cancer therapy. In the present study, we first investigated in silico the interaction of withanone, a withanolide with anticancer activity, with mortalin. We found that withanone could bind to mortalin in a region, earlier predicted critical for binding to p53. Cationic rhodacyanine dye, MKT-077 has also shown to bind the same region and kill cancer cells selectively. We report the molecular dynamic simulations revealing the thermodynamic and structural stability of the withanone-mortalin complexes. We also demonstrate the experimental evidence of abrogation of mortalin-p53 complex by withanone resulting in nuclear translocation and functional reactivation of p53 in human cancer cells. The present study establishes a molecular interaction basis that could be used for screening and development of anticancer drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of mortalin would further enhance the potential of such analyses to understand the molecular basis of mortalin biology and mortalin based cancer therapy.The international journal of biochemistry & cell biology 12/2011; 44(3):496-504. DOI:10.1016/j.biocel.2011.11.021 · 4.24 Impact Factor
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- "(Iuvone et al. 2003, Kaileh et al. 2007, Kuboyama et al. 2005, Widodo et al. 2007, Zhao et al. 2002 "
ABSTRACT: Ashwagandha (Withania somnifera Dunal., Solanaceae) is one of the most reputed medicinal plants of Ayurveda, the traditional medical system. Several of its traditionally proclaimed medicinal properties have been corroborated by recent molecular pharmacological investigations and have been shown to be associated with its specific secondary metabolites known as withanolides, the novel group of ergostane skeletal phytosteroids named after the plant. Withanolides are structurally distinct from tropane/nortropane alkaloids (usually found in Solanaceae plants) and are produced only by a few genera within Solanaceae. W. somnifera contains many structurally diverse withanolides in its leaves as well as roots. To date, there has been little biosynthetic or metabolism-related research on withanolides. It is thought that withanolides are synthesized in leaves and transported to roots like the tropane alkaloids, a group of bioactive secondary metabolites in Solanaceae members known to be synthesized in roots and transported to leaves for storage. To examine this, we have studied incorporation of (14)C from [2-(14)C]-acetate and [U-(14)C]-glucose into withanolide A in the in vitro cultured normal roots as well as native/orphan roots of W. somnifera. Analysis of products by thin layer chromatography revealed that these primary metabolites were incorporated into withanolide A, demonstrating that root-contained withanolide A is de novo synthesized within roots from primary isoprenogenic precursors. Therefore, withanolides are synthesized in different parts of the plant (through operation of the complete metabolic pathway) rather than imported.Physiologia Plantarum 07/2008; 133(2):278-87. DOI:10.1111/j.1399-3054.2008.01076.x · 3.26 Impact Factor