Inhibition of mTOR Signaling by Quercetin in Cancer Treatment and Prevention

Brüning, Ansgar

doi:10.2174/18715206113139990114

Cited by 100 publications

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“…Note that by day 3, proliferating preadipocytes increased by 2-5-fold in number vs. day 0 in the presence of D. The viability of nondividing, senescent preadipocytes from the same subjects decreased by 30–40% in the presence of 50 n m or greater D, indicating selective reduction in the viability of senescent cells. Q, a natural flavonol, inhibits PI3K, other kinases, and serpines (Olave et al ., 2010; Bruning, 2013). In contrast to D, at low concentrations, Q reduced the viability and caused cell death of senescent HUVECs to a greater extent than proliferating cells, but was less effective on preadipocytes (Fig 2…”

Section: Resultsmentioning

confidence: 99%

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

et al. 2015

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The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

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Section: Resultsmentioning

confidence: 99%

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

et al. 2015

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“…Many studies have suggested that several flavonoid compounds such as rutin and quercetin have strong antioxidant and anti-proliferative activities [5,6]. Recently, quercetin has attracted considerable attention as a potential anti-cancer agent and an inducer of autophagy [7,8]. Quercetin, as one of the most common flavonoids in nature, has been extensively studied as a chemoprevention agent in several cancer models due to its potent antioxidant, anti-tumor, and anti-inflammatory properties.…”

Section: Introductionmentioning

confidence: 99%

Changes of intracellular Ca<sup>2+</sup> in quercetin-induced autophagy progression

Cui

Luo

et al. 2015

ABBS

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Quercetin was previously reported to exhibit significant anti-proliferative activities, and its major effect on tumors was to induce cell apoptosis or autophagy. However, the specific mechanism remains controversial. In this study, autophagy induced by quercetin was determined with various methods. Intracellular Ca 2+ ([Ca 2+ ] i ) was measured after being incubated with Fluo-3 acetoxymethyl (AM). At the same time, the relationship between the intracellular Ca 2+ and autophagy induced by quercetin was further analyzed. These results showed that autophagy induced by quercetin (0-50 µg/ml) in HepG2 cells was in a dose-dependent manner. Meanwhile, when autophagy was induced by quercetin, [Ca 2+ ] i was significantly increased. And after being incubated with calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N-tetraacetic acid-AM, autophagy was suppressed, which implied that [Ca 2+ ] i elevation appeared to be the cause for autophagy induction. These results suggested that calcium from intracellular calcium storage may play an important role in quercetininduced autophagy.

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“…Specifically, we found that quercetin, kaempferol and progesterone acted on 162, 71 and 112 targets, respectively, and therefore could be the crucial pleiotropically active compounds for TFS owing to their crucial positioning in the network. Previously, several studies demonstrated that quercetin inhibited inflammation, enhanced immune function and promoted apoptosis by modulating key pathways regulating cancer, such as, prostaglandin G/H synthase 2, interleukin (IL)-2, peroxisome proliferator activated receptor gamma and caspase-9 [26, 27]. …”

Section: Resultsmentioning

confidence: 99%

Tianfoshen oral liquid: a CFDA approved clinical traditional Chinese medicine, normalizes major cellular pathways disordered during colorectal carcinogenesis

Wang

Wang²,

2017

Oncotarget

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Colorectal cancer remains the third leading cause of cancer death worldwide, suggesting exploration of novel therapeutic avenues may be useful. In this study, therefore, we determined whether Tianfoshen oral liquid, a Chinese traditional medicine that has been used to treat non-small cell lung cancer, would be therapeutically beneficial for colorectal cancer patients. Our data show that Tianfoshen oral liquid effectively inhibits growth of colorectal cancer cells both in vitro and in vivo. We further employed a comprehensive strategy that included chemoinformatics, bioinformatics and network biology methods to unravel novel insights into the active compounds of Tianfoshen oral liquid and to identify the common therapeutic targets and processes for colorectal cancer treatment. We identified 276 major candidate targets for Tianfoshen oral liquid that are central to colorectal cancer progression. Gene enrichment analysis showed that these targets were associated with cell cycle, apoptosis, cancer-related angiogenesis, and chronic inflammation and related signaling pathways. We also validated experimentally the inhibitory effects of Tianfoshen oral liquid on these pathological processes, both in vitro and in vivo. In addition, we demonstrated that Tianfoshen oral liquid suppressed multiple relevant key players that sustain and promote colorectal cancer, which is suggests the potential therapeutic efficacy of Tianfoshen oral liquid in future colorectal cancer treatments.

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Inhibition of mTOR Signaling by Quercetin in Cancer Treatment and Prevention

Cited by 100 publications

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The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Changes of intracellular Ca<sup>2+</sup> in quercetin-induced autophagy progression

Tianfoshen oral liquid: a CFDA approved clinical traditional Chinese medicine, normalizes major cellular pathways disordered during colorectal carcinogenesis

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Inhibition of mTOR Signaling by Quercetin in Cancer Treatment and Prevention

Cited by 100 publications

References 0 publications

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Changes of intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; in quercetin-induced autophagy progression

Tianfoshen oral liquid: a CFDA approved clinical traditional Chinese medicine, normalizes major cellular pathways disordered during colorectal carcinogenesis

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Changes of intracellular Ca<sup>2+</sup> in quercetin-induced autophagy progression