Silybins are stereospecific regulators of the 20S proteasome

Persico, Marco; García‐Viñuales, Sara; Santoro, Anna Maria; Lanza, Valeria; Tundo, Grazia R.; Sbardella, Diego; Coletta, M.; Romanucci, Valeria; Zarrelli, Armando; Fabio, Giovanni Di; Fattorusso, Caterina; Milardi, Danilo

doi:10.1016/j.bmc.2022.116813

Cited by 4 publications

(5 citation statements)

References 68 publications

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“…The results indicated that TpyCl was ineffective in inhibiting the chymotrypsin‐like (ChT‐L) activity of the proteasome, whereas [Cu(TpyCl) 2 ] 2+ was a mild 20S inhibitor (30 % of inhibition at a concentration of about 50 nM). As reported in Figure 6, the Cu(II) complex exhibits an inhibition profile with a minimum of 50 nM, as observed for other proteasome inhibitors [51–54] . Based on those early accounts, this behaviour suggests that the modulatory effects may be due to the occurrence of two different main mechanisms: i) at high concentration (micromolar range), the promotion of substrate entry into the catalytic chamber by inducing the opening of the α‐ring gate (gate openers), and ii) at lower concentrations, the inhibition of substrate binding to the catalytic pockets and degradation induced by allosteric interactions [54,55] …”

Section: Resultssupporting

confidence: 61%

“…ChT‐L proteasome activities were assayed in 50 μL of 25 mM TRIS buffer (pH 7.4) at 37 °C in the presence of the fluorogenic substrate (50 μM). Human 20S (2 nM) was incubated with Tpy compounds or its copper (II) complexes 1 : 2 (M/L ratio) for 45 min before enzymatic assays [51] . The compounds were tested at concentrations ranging from 0.5 nM to 5000 nM.…”

Section: Methodsmentioning

confidence: 99%

“…Human 20S (2 nM) was incubated with Tpy compounds or its copper (II) complexes 1 : 2 (M/L ratio) for 45 min before enzymatic assays. [51] The compounds were tested at concentrations ranging from 0.5 nM to 5000 nM. The fluorescence signal activated by peptide cleavage was recorded at 440 nm (excitation at 360 nm) for 45 min by a Varioskan (Thermo©) plate reader in 384 multiwell plates.…”

Section: Proteasome Activities Assaysmentioning

confidence: 99%

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Terpyridine Glycoconjugates and Their Metal Complexes: Antiproliferative Activity and Proteasome Inhibition

et al. 2023

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Metal terpyridine complexes have gained substantial interest in many application fields, such as catalysis and supramolecular chemistry. In recent years, the biological activity of terpyridine and its metal complexes has aroused considerable regard. On this basis, we synthesised new terpyridine derivatives of trehalose and glucose to improve the water solubility of terpyridine ligands and target them in cancer cells through glucose transporters. Glucose derivative and its copper(II) and iron(II) complexes showed antiproliferative activity. Interestingly, trehalose residue reduced the cytotoxicity of terpyridine. Moreover, we tested the ability of parent terpyridine ligands and their copper complexes to inhibit proteasome activity as an antineoplastic mechanism.

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Section: Resultssupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Proteasome Activities Assaysmentioning

confidence: 99%

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Terpyridine Glycoconjugates and Their Metal Complexes: Antiproliferative Activity and Proteasome Inhibition

et al. 2023

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“…[ 43 ] Here, we discovered that amino acid residues 40–47 and 103–113 showed significantly decreased H/D exchange efficiency, indicating that OA nanomicelles may promote the embedding of these regions within PMSA6 (Figure 4b,c). Interestingly, peptide 103–113 is close to the N‐terminal domain of PSMA6, which is responsible for the control of protein entry into the 20S proteasome for degradation [ 44 ] (Figure 4d).…”

Section: Resultsmentioning

confidence: 99%

Inherent Capability of Self‐Assembling Nanostructures in Specific Proteasome Activation for Cancer Cell Pyroptosis

Luo

et al. 2022

Small

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Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by targeting specific cellular proteins remains largely unknown. In the present work, self‐assembling nanomicelles are constructed using small‐molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N‐terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor‐bearing mouse models and stimulate immune cell infiltration. Collectively, this proof‐of‐concept study advances the mechanical understanding of nanostructure‐guided biological effects via their inherent capacity to activate proteasome.

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“…In this frame, our previous studies on the stereochemistry-activity relationship of silybins (SilA and SilB) revealed their features involved in the recognition of targets in AD and T2DM [30,31] as well as their ability to increase the proteasome activity [32], a multiattractive target involved in protein conformational diseases [33,34]. Without neglecting the stereochemical aspect and aiming at improving the pharmacokinetics of silybins, in the last few years, we have also designed new silybin pro-drugs containing hydrophilic moieties which did not significantly modify silybin activities [35,36].…”

Section: Introductionmentioning

confidence: 97%

7-O-tyrosyl Silybin Derivatives as a Novel Set of Anti-Prostate Cancer Compounds

Romanucci,

Pagano,

Kandhari

et al. 2024

Antioxidants

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Silybin is a natural compound extensively studied for its hepatoprotective, neuroprotective and anticancer properties. Envisioning the enhancement of silybin potential by suitable modifications in its chemical structure, here, a series of new 7-O-alkyl silybins derivatives were synthesized by the Mitsunobu reaction starting from the silybins and tyrosol-based phenols, such as tyrosol (TYR, 3), 3-methoxytyrosol (MTYR, 4), and 3-hydroxytyrosol (HTYR, 5). This research sought to explore the antioxidant and anticancer properties of eighteen new derivatives and their mechanisms. In particular, the antioxidant properties of new derivatives outlined by the DPPH assay showed a very pronounced activity depending on the tyrosyl moiety (HTYR > MTYR >> TYR). A significant contribution of the HTYR moiety was observed for silybins and 2,3-dehydro-silybin-based derivatives. According to the very potent antioxidant activity, 2,3-dehydro-silybin derivatives 15ab, 15a, and 15b exerted the most potent anticancer activity in human prostate cancer PC-3 cells. Furthermore, flow cytometric analysis for cell cycle and apoptosis revealed that 15ab, 15a, and 15b induce strong G1 phase arrest and increase late apoptotic population in PC-3 cells. Additionally, Western blotting for apoptotic marker cleaved caspase-3 confirmed apoptosis induction by these silybin derivatives in PC-3 cells. These findings hold significant importance in the investigation of anticancer properties of silybin derivatives and strongly encourage swift investigation in pre-clinical models and clinical trials.

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Silybins are stereospecific regulators of the 20S proteasome

Cited by 4 publications

References 68 publications

Terpyridine Glycoconjugates and Their Metal Complexes: Antiproliferative Activity and Proteasome Inhibition

Terpyridine Glycoconjugates and Their Metal Complexes: Antiproliferative Activity and Proteasome Inhibition

Inherent Capability of Self‐Assembling Nanostructures in Specific Proteasome Activation for Cancer Cell Pyroptosis

7-O-tyrosyl Silybin Derivatives as a Novel Set of Anti-Prostate Cancer Compounds

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