Probing the interaction of a quercetin bioconjugate with Bcl‐2 in living human cancer cells with in‐cell <scp>NMR</scp> spectroscopy

Primikyri, Alexandra; Sayyad, Nisar; Quilici, Giacomo; Vrettos, Eirinaios I.; Lim, Kyung-Eun; Chi, Seung‐Wook; Musco, Giovanna; Gerothanassis, Ioannis P.; Tzakos, Andreas G.

doi:10.1002/1873-3468.13250

Cited by 43 publications

(44 citation statements)

References 54 publications

(90 reference statements)

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“…Further, molecular docking experiments suggest that anti-apoptotic BCL2 family proteins (BCL2, BCL-xl and MCL1) could be directly inhibited by quercetin (Figure 9 and Table 2). A recent study showed that a quercetin–alanine conjugate directly binds to BCL2 and enhances apoptosis [61]. We believe that a similar interaction may be at play here.…”

Section: Discussionsupporting

confidence: 53%

Quercetin modulates signaling pathways and induces apoptosis in cervical cancer cells

Sundaram¹,

Raina²,

Afroze³

et al. 2019

Bioscience Reports

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Cancer cells have the unique ability to overcome natural defense mechanisms, undergo unchecked proliferation and evade apoptosis. While chemotherapeutic drugs address this, they are plagued by a long list of side effects and have a poor success rate. This has spurred researchers to identify safer bioactive compounds that possess chemopreventive and therapeutic properties. A wide range of experimental as well as epidemiological data encourage the use of dietary agents to impede or delay different stages of cancer. In the present study, we have examined the anti-ancer property of ubiquitous phytochemical quercetin by using cell viability assay, flow cytometry, nuclear morphology, colony formation, scratch wound assay, DNA fragmentation and comet assay. Further, qPCR analysis of various genes involved in apoptosis, cell cycle regulation, metastasis and different signal transduction pathways was performed. Proteome profiler was used to quantitate the expression of several of these proteins. We find that quercetin decreases cell viability, reduces colony formation, promotes G2-M cell cycle arrest, induces DNA damage and encourages apoptosis. Quercetin induces apoptosis via activating both apoptotic pathways with a stronger effect of the extrinsic pathway relying on the combined power of TRAIL, FASL and TNF with up-regulation of caspases and pro-apoptotic genes. Quercetin could inhibit anti-apoptotic proteins by docking studies. Further, quercetin blocks PI3K, MAPK and WNT pathways. Anticancer effect of quercetin observed in cell-based assays were corroborated by molecular biology studies and yielded valuable mechanistic information. Quercetin appears to be a promising candidate with chemopreventive and chemotherapeutic potential and warrants further research.

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Section: Discussionsupporting

confidence: 53%

Quercetin modulates signaling pathways and induces apoptosis in cervical cancer cells

Sundaram¹,

Raina²,

Afroze³

et al. 2019

Bioscience Reports

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“…Such observations could be attributed to the off-target binding in a multiple target environment. In addition to the target-observed in-cell NMR, the ligand-observed NMR can also be performed in vivo [164]. Donatella Potenza et al had conducted STD and trNOE experiments to validate the binding of specific compounds to integrin αvβ3 in ECV304 cells [165].…”

Section: In-cell Nmrmentioning

confidence: 99%

Applications of Solution NMR in Drug Discovery

Shi

Zhang

2021

Molecules

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During the past decades, solution nuclear magnetic resonance (NMR) spectroscopy has demonstrated itself as a promising tool in drug discovery. Especially, fragment-based drug discovery (FBDD) has benefited a lot from the NMR development. Multiple candidate compounds and FDA-approved drugs derived from FBDD have been developed with the assistance of NMR techniques. NMR has broad applications in different stages of the FBDD process, which includes fragment library construction, hit generation and validation, hit-to-lead optimization and working mechanism elucidation, etc. In this manuscript, we reviewed the current progresses of NMR applications in fragment-based drug discovery, which were illustrated by multiple reported cases. Moreover, the NMR applications in protein-protein interaction (PPI) modulators development and the progress of in-cell NMR for drug discovery were also briefly summarized.

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“…As FAAH is a membrane protein, the assay is feasible using this system, and compound fragments which were able to inhibit its activity were screened and confirmed [136]. The molecular interactions between Bcl-2 and the quercetin-alanine bioconjugate were investigated using proton-based NMR experiments [104]. This study shows that ligand-based NMR such as STD is also applicable in in-cell NMR.…”

Section: In-cell Nmr In Drug Discoverymentioning

confidence: 99%

Applications of In-Cell NMR in Structural Biology and Drug Discovery

Kang

2019

IJMS

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In-cell nuclear magnetic resonance (NMR) is a method to provide the structural information of a target at an atomic level under physiological conditions and a full view of the conformational changes of a protein caused by ligand binding, post-translational modifications or protein–protein interactions in living cells. Previous in-cell NMR studies have focused on proteins that were overexpressed in bacterial cells and isotopically labeled proteins injected into oocytes of Xenopus laevis or delivered into human cells. Applications of in-cell NMR in probing protein modifications, conformational changes and ligand bindings have been carried out in mammalian cells by monitoring isotopically labeled proteins overexpressed in living cells. The available protocols and successful examples encourage wide applications of this technique in different fields such as drug discovery. Despite the challenges in this method, progress has been made in recent years. In this review, applications of in-cell NMR are summarized. The successful applications of this method in mammalian and bacterial cells make it feasible to play important roles in drug discovery, especially in the step of target engagement.

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Probing the interaction of a quercetin bioconjugate with Bcl‐2 in living human cancer cells with in‐cell NMR spectroscopy

Cited by 43 publications

References 54 publications

Quercetin modulates signaling pathways and induces apoptosis in cervical cancer cells

Quercetin modulates signaling pathways and induces apoptosis in cervical cancer cells

Applications of Solution NMR in Drug Discovery

Applications of In-Cell NMR in Structural Biology and Drug Discovery

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