Withanolides represent an important category of natural products with a steroidal lactone core. Many of them contain an α,β-unsaturated carbonyl moiety with a high reactivity toward sulfhydryl groups, including protein cysteine thiols. Different withanolides endowed with marked antitumor and anti-inflammatory have been shown to form stable covalent complexes with exposed cysteines present in the active site of oncogenic kinases (BTK, IKKβ, Zap70), metabolism enzymes (Prdx-1/6, Pin1, PHGDH), transcription factors (Nrf2, NFκB, C/EBPβ) and other structural and signaling molecules (GFAP, β-tubulin, p97, Hsp90, vimentin, M^pro, IPO5, NEMO, …). The present review analyzed the covalent complexes formed through Michael addition alkylation reactions between six major withanolides (withaferin A, physalin A, withangulatin A, 4β-hydroxywithanolide E, withanone and tubocapsanolide A) and key cysteine residues of about 20 proteins and the resulting biological effects. The covalent conjugation of the α,β-unsaturated carbonyl system of withanolides with reactive protein thiols can occur with a large set of soluble and membrane proteins. It points to a general mechanism, well described with the leading natural product withaferin A, but likely valid for most withanolides harboring a reactive (electrophilic) enone moiety susceptible to react covalently with cysteinyl residues of proteins. The multiplicity of reactive proteins should be taken into account when studying the mechanism of action of new withanolides. Proteomic and network analyses shall be implemented to capture and compare the cysteine covalent-binding map for the major withanolides, so as to identify the protein targets at the origin of their activity and/or unwanted effects. Screening of the cysteinome will help understanding the mechanism of action and designing cysteine-reactive electrophilic drug candidates.

01 Jan 1995·Journal of Cellular BiochemistryQ3 · BIOLOGY

Integrity of intermediate filaments is associated with the development of acquired thermotolerance in 9L rat brain tumor cells

Q3 · BIOLOGY

Article

Author: Yu‐Chien Lee ; Yiu‐Kay Lai

AbstractWithangulatin A (WA), a newly discovered withanolide isolated from an antitumor Chinese herb, has been shown to be a vimentin intermediate filament‐targeting drug by using immunofluorescence microscopy. Together with cytochalasin D and colchicine, these drugs were employed to investigate the importance of vimentin intermediate filaments, actin filaments, and microtubules in the development of acquired thermotolerance in 9L rat brain tumor cells treated at 45°C for 15 min (priming heat‐shock). Acquired thermotolerance was abrogated in cells incubated with WA before the priming heat‐shock but it could be detected in cells treated with WA after the priming heat‐shock. In contrast, cytochalasin D and colchicine do not interfere with the development of thermotolerance at all. The intracellular localizations of vimentin and the constitutive heat‐shock protein70 (HSC70) in treated cells were examined by using immunofluorescence microscopy and detergent‐extractability studies. In cells treated with WA before the priming heat‐shock, vimentin IFs were tightly aggregated around the nucleus and unable to return to their normal organization after a recovery under normal growing conditions. In contrast, the IF network in cells treated with WA after the priming heat‐shock was able to reorganize into filamentous form after a recovery period, a behavior similar to that of the cells treated with heat‐shock only. HSC70 was found to be co‐localized with vimentin during these changes. It is suggested that the integrity of intermediate filaments is important for the development of thermotolerance and that HSC70 may be involved in this process by stabilizing the intermediate filaments through direct or indirect binding.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	TW	National Tsing-Hua University	01 Mar 1989

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