Quercetin Induces Antiproliferative Activity Against Human Hepatocellular Carcinoma (HepG2) Cells by Suppressing Specificity Protein 1 (Sp1)

Lee, Ra Ham; Cho, Jin Hyoung; Jeon, Young‐Joo; Bang, Woong; Cho, Jung-Jae; Choi, Nak Hwan; Seo, Kang Seok; Shim, Jung‐Hyun; Chae, Jung‐Il

doi:10.1002/ddr.21235

Cited by 31 publications

(18 citation statements)

References 29 publications

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“…In addition to ephrins, other dependence receptor ligands, PI3K, AKT, and serpines, we anticipate that drugs that target p21, probably p53 and MDM2 (because they regulate p21 and serpines), BCL-xL, and related genes will also have senolytic effects. This is especially so as existing drugs that act through these targets cause apoptosis in cancer cells and are in use or in trials for treating cancers, including dasatinib, quercetin, and tiplaxtinin (Gomes-Giacoia et al ., 2013; Truffaux et al ., 2014; Lee et al ., 2015). …”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…Jeon et al reported an increase in p53 levels and a decrease in cyclin A and checkpoint kinase 1 (CHK1) expression in HepG2 cells after quercetin treatment [25], while this drug downregulated p53 and enhanced G0/G1 and G2/M populations in HepG2 and HuH7 HCC lines [51]. Augmented levels of p21 and p27, cell cycle inhibitors, and cyclin D1 reduction were observed in another study with HepG2 cells [33] and it has been also shown that quercetin promoted G0/G1-phase arrest [49,52,53] through upregulating p16, p21 and p53 [53]. Conversely, a cell cycle arrest at G2/M phase has been described as a quercetin effect against HCC cell proliferation in HepG2 [30] and LM3 liver cancer lines [22].…”

Section: Antitumor Properties Of Quercetin As Single Agent Against Hccmentioning

confidence: 94%

“…Quercetin antitumor effects have been described in different cancer types, including HCC [1]. In 25 of the articles included in the present review, quercetin efficacy as single treatment was evaluated employing different HCC study models [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]46,48,49,[51][52][53][54]57]. Antiproliferative effect of this flavonoid alone has been demonstrated in several researches with in vitro models [22][23][24][25][26][27][30][31][32][33]35,38,46,48,49,[51][52][53][54], highlighting the HepG2 cell line as the most used in 21 of the 25 articles [24,25,<...>…”

Section: Antitumor Properties Of Quercetin As Single Agent Against Hccmentioning

confidence: 99%

“…Induction of p53 as consequence of phosphatidyl inositol 3 kinase (PI3K) and protein kinase C (PKC) downregulation was also linked to antiproliferative effects in liver tumor cells [31], in addition to the blockade of Src homology domain 2 containing tyrosine phosphatase-1/2 (SHP-1/2) activity through directly interacting with quercetin [48]. A group of researchers also observed that this flavonoid was able to abrogate the transcription factor specificity protein 1 (Sp1) expression leading to suppression of HepG2 cell proliferation [33], thus increasing the number of cellular pathways that may be altered by quercetin.…”

Section: Antitumor Properties Of Quercetin As Single Agent Against Hccmentioning

confidence: 99%

“…Otherwise, though cell cycle regulation is a common mechanism found to be altered in HCC cells, only eight publications have evaluated the effects of quercetin in this process, showing contradictory results [22,25,30,33,49,[51][52][53]. Jeon et al reported an increase in p53 levels and a decrease in cyclin A and checkpoint kinase 1 (CHK1) expression in HepG2 cells after quercetin treatment [25], while this drug downregulated p53 and enhanced G0/G1 and G2/M populations in HepG2 and HuH7 HCC lines [51].…”

Section: Antitumor Properties Of Quercetin As Single Agent Against Hccmentioning

confidence: 99%

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Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

et al. 2019

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Quercetin is a flavonoid present in fruits, vegetables and plants with antioxidant, anti-inflammatory and anticancer properties. Its beneficial activities have been demonstrated in different human pathologies, including hepatoprotective effects against liver disorders. High mortality and late diagnosis of the primary liver tumor hepatocarcinoma (HCC) makes this cancer an interesting target for the study of quercetin effects. Our aim was to systematically review antitumor activities of quercetin in HCC preclinical studies employing single, encapsulated, combined or derived quercetin forms. Literature search was conducted in PubMed, Scopus and Web of Science (WOS), and 39 studies were finally included. We found that 17 articles evaluated quercetin effects alone, six used encapsulated strategy, 10 combined this flavonoid, two decided to co-encapsulate it and only four studied effects of quercetin derivatives, highlighting that only nine included in vivo models. Results evidence the quercetin antiproliferative and proapoptotic properties against HCC either alone and with the mentioned strategies; nevertheless, few investigations assessed specific activities on different processes related with cancer progression. Overall, further studies including animal models are needed to deeper investigate the precise mechanisms of action of quercetin as antitumor agent, as well as the potential of novel strategies aimed to improve quercetin effects in HCC.

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Quercetin shows anti‐tumor effect in hepatocellular carcinoma LM3 cells by abrogating JAK2/STAT3 signaling pathway

Liu

et al. 2019

Cancer Medicine

140

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Objective Hepatocellular carcinima is one of the most common tumors in clinic and also one of the leading causes of death from cancer worldwide. Quercetin shows significant effects on blocking the development of various cancers. Methods We used the human hepatocellular carcinoma LM3 and nude mice tumor model to assess the effects of quercetin in hepatocellular carcinoma and clarify its mechanism of action. We collected LM3 cell line treated with different doses of quercetin at different time periods and determined the vital indexes. The liver tissues of mice were collected and used for western boltting (WB), Hematoxylin and Eosin (H&E) and TUNEL staining. Results Results indicated that quercetin suppressed the Hepatocellular carcinoma (HCC) growth both in vivo and in vitro. Quercetin could disturb LM3 cells proliferation and cell cycle distribution, thus inducing apoptosis. At the same time, quercetin inhibited LM3 cells migration and invasion and promoted HCC autophagy. These effects at least partly depended on the down‐regulation of the activation of JAK2 and STAT3 by quercetin. Conclusion Quercetin inhibited hepatocellular carcinoma progression by modulating cell apoptosis, migration, invasion, and autophagy; and its effects were at least partly related with the JAK2/STAT3 signaling pathway.

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Quercetin Induces Antiproliferative Activity Against Human Hepatocellular Carcinoma (HepG2) Cells by Suppressing Specificity Protein 1 (Sp1)

Cited by 31 publications

References 29 publications

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

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

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

Quercetin shows anti‐tumor effect in hepatocellular carcinoma LM3 cells by abrogating JAK2/STAT3 signaling pathway

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