2, 3-Dihydrowithaferin A-3β-O-sulfate, a new potential prodrug of withaferin A from aeroponically grown Withania somnifera
Abstract
Preparations of the roots of the medicinal plant Withania somnifera (L.) Dunal commonly called ashwagandha have been used for millennia in the Ayurvedic medical tradition of India as a general tonic to relieve stress and enhance health, especially in the elderly. In modern times, ashwagandha has been shown to possess intriguing antiangiogenic and anticancer activity, largely attributable to the presence of the steroidal lactone withaferin A as the major constituent. When cultured using the aeroponic technique, however, this plant was found to produce a new natural product, 2,3-dihydrowithaferin A-3beta-O-sulfate (1), as the predominant constituent of methanolic extracts prepared from aerial tissues. The characteristic bioactivities exhibited by 1 including inhibition of cancer cell proliferation/survival, disruption of cytoskeletal organization and induction of the cellular heat-shock response paralleled those displayed by withaferin A (2). The delayed onset of action and reduced potency of 1 in cell culture along with previous observations demonstrating the requirement of the 2(3)-double bond in withanolides for bioactivity suggested that 1 might be converted to 2 in cell culture media and this was confirmed by HPLC analysis. The abundant yield of 1 from aeroponically cultivated plants, its good aqueous solubility and spontaneous conversion to 2 under cell culture conditions, suggest that 1 could prove useful as a readily formulated prodrug of withaferin A that merits further evaluation in animal models.
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Aqueous root extract of WS reduced Tilapia lake virus (TiLV)-mediated stress level and mortality.
“Alongside COVID-19, an aqueous root extract of WS also reduced the Tilapia lake virus (TiLV) mediated stress level and mortality [388].”
From Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects (2021) · cites this paper as [388]
Cites
1 retracted
RETRACTED: Adaptogenic and cardioprotective action of ashwagandha in rats and frogs
Dhuley, J. N. (2000) · Journal of Ethnopharmacology · doi:10.1016/s0378-8741(99)00177-4 · Cited by 129 · see citing works
RetractedHSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502 · see citing works
Self-citationAdapting Proteostasis for Disease Intervention
Balch, W. E., Morimoto, R. I., Dillin, A., & Kelly, J. W. (2008) · Science · doi:10.1126/science.1141448 · Cited by 2,495 · see citing works
Studies in Natural Products Chemistry
(1993) · Studies in natural products chemistry · doi:10.1016/b978-0-444-89366-6.70001-0 · Cited by 1,743 · see citing works
Heat Shock Factor 1 Is a Powerful Multifaceted Modifier of Carcinogenesis
Dai, C., Whitesell, L. J., Rogers, A. B., & Lindquist, S. L. (2007) · Cell · doi:10.1016/j.cell.2007.07.020 · Cited by 827 · see citing works
Self-citationMcMillan, D. R., Xiao, X., Shao, L., Graves, K. H., & Benjamin, I. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.13.7523 · Cited by 524 · see citing works
Studies on the immunomodulatory effects of Ashwagandha
Ziauddin, M., Phansalkar, N., Patki, P. S., Diwanay, S. S., & Patwardhan, B. (1996) · Journal of Ethnopharmacology · doi:10.1016/0378-8741(95)01318-0 · Cited by 382 · see citing works
Bargagna‐Mohan, P., Hamza, A., Kim, Y.-E., Ho, Y. K., Mor‐Vaknin, N., Wendschlag, N., Liu, J., Evans, R. M., Markovitz, D. M., Zhan, C., et al. (2007) · Chemistry & Biology · doi:10.1016/j.chembiol.2007.04.010 · Cited by 348 · see citing works
Kaileh, M., Berghe, W. V., Heyerick, A., Horion, J., Piette, J. G., Libert, C., Keukeleire, D. D., Essawi, T. A., & Haegeman, G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606728200 · Cited by 303 · see citing works
Par-4-Dependent Apoptosis by the Dietary Compound Withaferin A in Prostate Cancer Cells
Srinivasan, S., Ranga, R. S., Burikhanov, R., Han, S., & Damodaran, C. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2430 · Cited by 231 · see citing works
Yang, H., Shi, G., & Dou, Q. P. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.030015 · Cited by 227 · see citing works
Effect of ashwagandha on lipid peroxidation in stress-induced animals
Dhuley, J. N. (1998) · Journal of Ethnopharmacology · doi:10.1016/s0378-8741(97)00151-7 · Cited by 157 · see citing works
Turbyville, T. J., Wijeratne, E. M. K., Liu, M. X., Burns, A. M., Seliga, C. J., Luevano, L. A., David, C. L., Faeth, S. H., Whitesell, L. J., & Gunatilaka, A. A. L. (2006) · Journal of Natural Products · doi:10.1021/np058095b · Cited by 150 · see citing works
Self-citationActin microfilament aggregation induced by withaferin A is mediated by annexin II
Falsey, R. R., Marron, M. T., Gunaherath, G. M. K. B., et al. (2005) · Nature Chemical Biology · doi:10.1038/nchembio755 · Cited by 143 · see citing works
Self-citationEffect of some Indian herbs on macrophage functions in ochratoxin A treated mice
Dhuley, J. N. (1997) · Journal of Ethnopharmacology · doi:10.1016/s0378-8741(97)00072-x · Cited by 138 · see citing works
Sen, N., Banerjee, B., Das, B. B., Ganguly, A., Sen, T., Pramanik, S. K., Mukhopadhyay, S., & Majumder, H. K. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402002 · Cited by 113 · see citing works
Aeroponic and Hydroponic Systems for Medicinal Herb, Rhizome, and Root Crops
Hayden, A. L. (2006) · HortScience · doi:10.21273/hortsci.41.3.536 · Cited by 99 · see citing works
Widodo, N., Takagi, Y., Shrestha, B. G., Ishii, T., Kaul, S. C., & Wadhwa, R. (2008) · Cancer Letters · doi:10.1016/j.canlet.2007.11.037 · Cited by 96 · see citing works
Unusually sulfated and oxygenated steroids from Withania somnifera
Misra, L., Lal, P., Sangwan, R. S., et al. (2005) · Phytochemistry · doi:10.1016/j.phytochem.2005.10.001 · Cited by 94 · see citing works
Phytochemical and genetic analysis in selected chemotypes of Withania somnifera
Dhar, R. S., Verma, V., Suri, K. A., et al. (2006) · Phytochemistry · doi:10.1016/j.phytochem.2006.07.014 · Cited by 93 · see citing works
Kupchan, S. M., Doskotch, R. W., Bollinger, P., et al. (1965) · Journal of the American Chemical Society · doi:10.1021/ja00952a061 · Cited by 93 · see citing works
Devi, P. U., Sharada, A. C., & Solomon, F. E. (1993) · PubMed · Cited by 87 · see citing works
Devi, P. U., Sharada, A. C., & Solomon, F. E. (1995) · Cancer Letters · doi:10.1016/0304-3835(95)03892-z · Cited by 80 · see citing works
Khajuria, R. K., Suri, K. A., Gupta, R. K., et al. (2004) · Journal of Separation Science · doi:10.1002/jssc.200301690 · Cited by 72 · see citing works
Wijeratne, E. M. K., Turbyville, T. J., Zhang, Z., et al. (2003) · Journal of Natural Products · doi:10.1021/np030266u · Cited by 70 · see citing works
Influence of an Indian medicine (Ashwagandha) on acute-phase reactants in inflammation.
Anbalagan, K., & Sadique, J. (1981) · PubMed · Cited by 69 · see citing works
Toxicity of Withania Somnifera Root Extract in Rats and Mice
Sharada, A. C., Solomon, F. E., & Devi, P. U. (1993) · Pharmaceutical Biology · doi:10.3109/13880209309082943 · Cited by 62 · see citing works
Fuska, J., Fusková, A., Rosazza, J. P. N., et al. (1984) · PubMed · Cited by 51 · see citing works
Lee, W., Lin, K., Chen, C., Chen, Z., Hon-Ju, L., & Lai, Y. (1991) · Journal of Cellular Physiology · doi:10.1002/jcp.1041490110 · Cited by 33 · see citing works
Shohat, B., & Joshua, H. (1971) · International Journal of Cancer · doi:10.1002/ijc.2910080317 · Cited by 29 · see citing works
Viscosalactone A and Viscosalactone B, Two New Steroidal Lactones from Physalis viscosa
Pelletier, S. W., Gebeyehu, G., Nowacki, J., et al. (1981) · Heterocycles · doi:10.3987/s-1981-01-0317 · Cited by 27 · see citing works
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Paul, S., Chakraborty, S., Anand, U., Dey, S., Nandy, S., Ghorai, M., Saha, S. C., Patil, M. T., Kandimalla, R., Proćków, J., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112175 · Cited by 306 · see citing works
- Authors
- Xu, Y.-M., Marron, M. T., Seddon, E., McLaughlin, S. P., Ray, D. T., Whitesell, L., & Leslie Gunatilaka, A. A.
- Affiliations
- University of Arizona (US)
- Whitehead Institute for Biomedical Research (US)
- Venue
- Bioorganic & Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 17
- Issue
- 6
- Pages
- 2210-2214
- ISSN
- 0968-0896 (ISSN-L)
- OpenAlex
- W2165810298
- Cited by
- 75
- References
- 31
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 6
- FWCI
- 12.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant tissue culture and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
- Keywords
- withaferin A, prodrugs, Withania somnifera, withanolides, steroidal lactones, anticancer activity, antiangiogenic activity, heat shock response, cytoskeleton disruption, cancer cell proliferation inhibition, natural product discovery
- MeSH terms
- Ergosterol, Humans, Magnetic Resonance Spectroscopy, Prodrugs, Spectrometry, Mass, Electrospray Ionization, Withania, Cell Line, Tumor, Withanolides
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