Direct Binding of Bcl-2 Family Proteins by Quercetin Triggers Its Pro-Apoptotic Activity

Primikyri, Alexandra; Chatziathanasiadou, Μaria V.; Karali, Evdoxia; Kostaras, Eleftherios; Mantzaris, Michalis D.; Hatzimichael, Eleftheria; Shin, Jeong Hyun; Chi, Seung‐Wook; Briasoulis, Evangelos; Kolettas, Evangelos; Gerothanassis, Ioannis P.; Tzakos, Andreas G.

doi:10.1021/cb500259e

Cited by 64 publications

(47 citation statements)

References 28 publications

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“…The Bcl-2 family includes pro-apoptotic and anti-apoptotic members. Pro-apoptotic Bcl-2-like proteins, including Bax, promote apoptosis by opening the mitochondrial voltage-dependent anion channel to cause permeabilization of the mitochondrial outer membrane and the release of other pro-apoptotic factors (19). In the present study, celastrol treatment increased Fas, FADD, TRADD, TNF-R1 and DR5 expression and reduced the mitochondrial membrane potential (Fig.…”

Section: Discussionsupporting

confidence: 57%

Celastrol-induced apoptosis in human nasopharyngeal carcinoma is associated with the activation of the death receptor and the mitochondrial pathway

et al. 2017

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Abstract. Nasopharyngeal carcinoma (NPC) is a cancer that arises from the epithelium of the nasopharynx. Celastrol is a triterpene from traditional Chinese medicine, which demonstrates anti-proliferative activity in several cancer cell lines. However, the effect of celastrol on human NPC and the underlying mechanisms are not yet elucidated. The present study investigated whether celastrol induced apoptosis in human NPC cells, and the underlying molecular mechanisms were explored. Celastrol decreased the viability of HONE-1 and NPC-039 cells in a dose-dependent manner, and induced G1 and G2/M phase cell cycle arrest. The level of cleaved caspases-3, -8, and -9 and poly (ADP-ribose) polymerase 1 increased in cells treated with celastrol. There was an increase in active Bcl-2-like 11 isoform S, Bcl-2-associated X, Bcl-2 antagonist/killer and truncated BH3-interacting death antagonist, and the levels of the anti-apoptotic Bcl-2 and Bcl-2-like 1 decreased. Celastrol induced an increase in Fas, Fas-associated via death domain, TNF receptor superfamily members (TNRSF) 1A and 10B, and TNFRSF1A associated via death domain, and induced a dose-dependent reduction in mitochondrial membrane potential. Celastrol inhibited activation of mitogen-activated protein kinase (MAPK) 1/3 and 14, and induced MAPK 8/9 activation. The results indicated that celastrol induced apoptosis through the death receptor and the mitochondrial pathway in human NPC cells, and is a promising candidate in the development of drugs against NPC. IntroductionNasopharyngeal carcinoma (NPC) is a cancer that arises from the epithelium of nasopharynx. This cancer is uncommon in Europe and America, and its incidence is higher in Africa and Southeast Asia (1). Its unique epidemiology, pathogenesis and association with the Epstein-Barr virus make it distinct from other types of head and neck cancer. Although NPC is reported to respond well to radiation therapy, chemotherapy also has a function in the current treatment protocol (2). For cases that have spread beyond the nasopharynx (i.e., cancer stages II, III, IVA and IVB), the addition of chemotherapy is common. Typically, platinum based agents, including cisplatin or carboplatin are used to treat NPC alongside fluorouracil (3). However, these medications also harm normal cells, causing side effects that include a decrease in white blood cells, anemia, kidney toxicity and nausea.Apoptosis, the process of programmed cell death, is a crucial self-defense mechanism for the human body to counteract cancerous cells. A number of existing chemotherapeutic agents aim to initiate the apoptosis cascade for an anti-tumor effect (4,5). However, as the disease progresses, certain cancer cell populations become resistant to chemotherapeutic agents and the efficacy of chemotherapy gradually deteriorates. Therefore, developing novel chemotherapeutic agents against NPC is crucial.Tripterygium wilfordii, also known as thunder god vine, is an herb traditionally used in Asia to treat various diseases, including tissue inflammation...

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Section: Discussionsupporting

confidence: 57%

Celastrol-induced apoptosis in human nasopharyngeal carcinoma is associated with the activation of the death receptor and the mitochondrial pathway

et al. 2017

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“…recently, it has been described the capacity of quercetin to directly bind the BH3 domain of Bcl-2 and Bcl-X L proteins, inhibiting their activity and promoting cancer cell apoptosis. Structural similarities seem to exist in the interactions between the Bcl-X L /quercetin compared to Bcl-X L /ABT-737 complexes, showing that quercetin can bind to Bcl-X L as ABT-737 [79]. This latter approach, although largely based on in vitro data, opens new perspectives to the interpretation of the mechanism of action of quercetin in B-CLL and deserves further investigations.…”

Section: Discussionmentioning

confidence: 99%

CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia

et al. 2017

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Despite the encouraging results of the innovative therapeutic treatments, complete remission is uncommon in patients affected by chronic lymphocytic leukaemia, which remains an essentially incurable disease. Recently, clinical trials based on BH3-mimetic drugs showed positive outcomes in subjects with poor prognostic features. However, resistance to treatments occurs in a significant number of patients. We previously reported that the multi-kinase inhibitor quercetin, a natural flavonol, restores sensitivity to ABT-737, a BH3-mimetic compound, in both leukemic cell lines and B-cells isolated from patients. To identify the molecular target of quercetin, we employed a new cell line, HG3, obtained by immortalization of B-cells from a chronic lymphocytic leukaemia patient at the later stage of disease. We confirmed that quercetin in association with ABT-737 synergistically enhances apoptosis in HG3 (combination index < 1 for all fractions affected). We also reported that the cellular uptake of quercetin is extremely rapid, with an intracellular concentration of about 38.5 ng/106 cells, after treatment with 25 μM for 5 min. We demonstrated that the activity of protein kinase CK2, which positively triggers PI3K/Akt pathway by inactivating PTEN phosphatase, is inhibited by quercetin immediately after its addition to HG3 cells (0–2 min). PI3K activity was also inhibited by quercetin within 60 min from the treatment. The combined inhibition of CK2 and PI3K kinase activities by quercetin restored ABT-737 sensitivity and increased lethality in human leukemia cells.

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“…Human T‐cell leukemic Jurkat Puro and Jurkat Bcl‐2 cells were stably generated by retroviral infection of Jurkat cells, using either a control puromycin retrovector or the same retrovector carrying a human Bcl‐2 cDNA, respectively . Cells were cultured as previously reported .…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we determined the basis of the pro‐apoptotic activity of quercetin in human T‐leukemia cells to be due to direct interaction with Bcl‐2 antiapoptotic proteins . Specifically, quercetin exhibited BH3‐mimetic properties and could directly bind to the BH3 domain of Bcl‐2 and Bcl‐xL proteins with a K d of 1.1 μ m , suggesting it as a potential mechanism for driving cancer cells to apoptosis . However, the main drawbacks of quercetin are its limited water solubility and cell selectivity that hamber its administration as a chemo‐preventer .…”

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confidence: 99%

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

Primikyri

Sayyad

Quilici³

et al. 2018

FEBS Letters

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In-cell NMR spectroscopy has emerged as a powerful technique for monitoring biomolecular interactions at an atomic level inside intact cells. However, current methodologies are inadequate at charting intracellular interactions of nonlabeled proteins and require their prior isotopic labeling. Herein, we describe for the first time the monitoring of the quercetin-alanine bioconjugate interaction with the nonlabeled antiapoptotic protein Bcl-2 inside living human cancer cells. STD and Tr-NOESY in-cell NMR methodologies were successfully applied in the investigation of the binding, which was further validated in vitro. In-cell NMR proved a very promising strategy for the real-time probing of the interaction profile of potential drugs with their therapeutic targets in native cellular environments and could, thus, open a new avenue in drug discovery.

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Direct Binding of Bcl-2 Family Proteins by Quercetin Triggers Its Pro-Apoptotic Activity

Cited by 64 publications

References 28 publications

Celastrol-induced apoptosis in human nasopharyngeal carcinoma is associated with the activation of the death receptor and the mitochondrial pathway

Celastrol-induced apoptosis in human nasopharyngeal carcinoma is associated with the activation of the death receptor and the mitochondrial pathway

CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia

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

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