Liquiritigenin Inhibits Colorectal Cancer Proliferation, Invasion, and Epithelial-to-Mesenchymal Transition by Decreasing Expression of Runt-Related Transcription Factor 2

Meng, Fan-Chun; Lin, Jun-Kai

doi:10.3727/096504018x15185747911701

Cited by 35 publications

(24 citation statements)

References 29 publications

(11 reference statements)

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“…Liquiritigenin, a flavonoid extracted from the roots of Glycyrrhiza uralensis Fisch, inhibited HCT116 colorectal cancer cells invasion and EMT by reduction of Runt-Related Transcription Factor 2 (Runx2) and inactivation of PI3K/AKT signaling [ 89 ].…”

Section: Targeting Metastatic Cancermentioning

confidence: 99%

Flavonoids in Cancer Metastasis

Líšková

Koklesová

Samec

et al. 2020

Cancers

132

135

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Metastasis represents a serious complication in the treatment of cancer. Flavonoids are plant secondary metabolites exerting various health beneficiary effects. The effects of flavonoids against cancer are associated not only with early stages of the cancer process, but also with cancer progression and spread into distant sites. Flavonoids showed potent anti-cancer effects against various cancer models in vitro and in vivo, mediated via regulation of key signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of epithelial-mesenchymal transition or regulatory molecules such as MMPs, uPA/uPAR, TGF-β and other contributors of the complex process of metastatic spread. Moreover, flavonoids modulated also the expression of genes associated with the progression of cancer and improved inflammatory status, a part of the complex process involved in the development of metastasis. Flavonoids also documented clear potential to improve the anti-cancer effectiveness of conventional chemotherapeutic agents. Most importantly, flavonoids represent environmentally-friendly and cost-effective substances; moreover, a wide spectrum of different flavonoids demonstrated safety and minimal side effects during long-termed administration. In addition, the bioavailability of flavonoids can be improved by their conjugation with metal ions or structural modifications by radiation. In conclusion, anti-cancer effects of flavonoids, targeting all phases of carcinogenesis including metastatic progression, should be implemented into clinical cancer research in order to strengthen their potential use in the future targeted prevention and therapy of cancer in high-risk individuals or patients with aggressive cancer disease with metastatic potential.

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Section: Targeting Metastatic Cancermentioning

confidence: 99%

Flavonoids in Cancer Metastasis

Líšková

Koklesová

Samec

et al. 2020

Cancers

132

135

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“…Pharmacological studies have demonstrated antioxidant, anti-tumor, antitussive, anti-inflammatory, antiosteoporosis, anti-ulcerative colitis, detoxification, and neuroprotective activities of GR (Lee et al, 2012; Shi et al, 2014; Jeon et al, 2016; Rho et al, 2017). Several chemical components isolated from GR, including glycyrrhizin, liquiritigenin, and liquiritin, have been reported to possess anti-cancer activities that induce apoptosis and inhibit invasion (Huang et al, 2014; Wei et al, 2017; He et al, 2017; Meng and Lin, 2018). Another active component, isoliquiritin apioside (ISLA), showed marked modulatory activities against oxidative-stress-induced genotoxicity and significantly inhibited tetanic contractions of rat gastrocnemius muscles (Kaur et al, 2009; Lee et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Isoliquiritin Apioside Suppresses in vitro Invasiveness and Angiogenesis of Cancer Cells and Endothelial Cells

Kim

Yeul

2018

Front. Pharmacol.

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Several components isolated from Glycyrrhizae radix rhizome (GR), including glycyrrhizin, liquiritin, and liquiritigenin, have been shown to induce cancer cell death and inhibit cancer metastasis. Isoliquiritin apioside (ISLA), a component isolated from GR, has been effective for treating tetanic contraction and genotoxicity. However, the effects of ISLA on the metastasis and angiogenesis of malignant cancer cells and endothelial cells (ECs) have not been reported. In this study, we found that up to 100 μM ISLA did not affect cell proliferation but efficiently suppressed the metastatic ability of HT1080 cells, as assessed by scratch-wound migration, Transwell® migration, scratch-wound invasion, Transwell® invasion, and three-dimensional spheroid invasion. ISLA significantly decreased phorbol 12-myristate 13-acetate (PMA)-induced increases in matrix metalloproteinase (MMP) activities and suppressed PMA-induced activation of mitogen-activated protein kinase as well as NF-κB, which are involved in cancer metastasis. In addition, ILSA treatment reduced the production of pro-angiogenic factors in HT1080 cells, including MMP-9, placental growth factor, and vascular endothelial growth factor under normoxia as well as hypoxia conditions, by impairing the hypoxia-inducible factor-1α pathway. We also found that the abilities of human umbilical vein ECs to migrate across the Transwell® and to form tube-like structures were significantly reduced by ISLA treatment. Moreover, using the chorioallantoic membrane assay, vessel formation with or without vascular endothelial growth factor was significantly suppressed by ISLA. These results suggested that ISLA possesses anti-metastatic and anti-angiogenic abilities in malignant cancer cells and ECs, with no cytotoxicity. ISLA may therefore be a safe and effective lead compound to develop anti-cancer drug for limiting the spread of primary tumors to distant organs to form secondary tumors.

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“…These results align with those of a previous study suggesting that liquiritigenin inhibits proliferation, invasion, and EMT of colorectal cancer cells. 12 Moreover, similar to its pro-apoptotic and inhibition effects on EMT in HCT116 cells, 12 as well as its inhibitory effects on invasion and metastasis of B16F10 melanoma cells, 17 liquiritigenin treatment also enhanced Caspase3 activity, upregulated E-cadherin, and downregulated N-cadherin, vimentin, and MMP9 expression in both MDA-MB-231 and BT549 cells. These findings suggest that liquiritigenin can inhibit the occurrence and development of breast cancer by reducing cellular proliferation, inducing apoptosis, and inhibiting cell invasion and migration.…”

Section: Discussionmentioning

confidence: 93%

“…2,9,10 Moreover, epidemiological studies show a negative correlation between breast cancer risk and flavonoid intake. 11 Liquiritigenin is a natural flavonoid isolated from Glycyrrhizae radix that exhibits various pharmacological effects, including estrogenic, 12 anti-oxidative, 13 anti-inflammatory, 14 and anti-tumor activities. 15 Liquiritigenin reportedly restrains proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) of colorectal cancer HCT116 cells.…”

Section: Introductionmentioning

confidence: 99%

“…15 Liquiritigenin reportedly restrains proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) of colorectal cancer HCT116 cells. 12 Through inhibiting VEGF, liquiritigenin reduces angiogenesis and tumor growth, a mouse model of HeLa cells. 16 In B16F10 melanoma cells and mice model, liquiritigenin reportedly potentiates cisplatin-mediated inhibitory effects on invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

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Liquiritigenin decreases tumorigenesis by inhibiting DNMT activity and increasing BRCA1 transcriptional activity in triple-negative breast cancer

Liang

Zhang

Gao

et al. 2020

Exp Biol Med (Maywood)

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As a selective estrogen receptor β agonist, the natural flavonoid liquiritigenin reportedly inhibits invasiveness of breast cancer cells, but its specific role and mechanism remain largely unclear. In this study, cells from the triple negative breast cancer lines MDA-MB-231 and BT549 were incubated with different concentrations of liquiritigenin. The results indicated that low concentrations had no significant cytotoxic effect, whereas high concentrations decreased viability of both MDA-MB-231 and BT549 cells. Liquiritigenin treatment also resulted in increased apoptosis and enhanced Caspase3 activity. After liquiritigenin treatment, we observed decreased invasive and migratory capacities of cells, as well as upregulated E-cadherin and downregulated N-cadherin, vimentin, and MMP9. Interestingly, liquiritigenin increased the mRNA and protein expression of breast cancer 1 (BRCA1). It also increased p21 and growth arrest and DNA-damage-inducible 45 alpha (GADD45A) levels, accompanied by decreased cellular DNA methyltransferase (DNMT) activity and downregulation of DNMT1, DNMT3a, and DNMT3b. These findings suggest that liquiritigenin can inhibit malignant behavior of triple negative breast cancer cells by inhibiting DNMT activity and increasing BRCA1 expression and its transcriptional activity. Liquiritigenin thus may be a promising candidate for the treatment of breast cancer. Impact statement Triple negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis and higher metastatic rates and relapse frequencies than other breast cancers. Natural flavonoid liquiritigenin reportedly inhibits invasiveness of TNBC MDA-MB-231 cells, but its specific role and mechanism remain unclear. This study administered different doses of liquiritigenin into TNBC cell lines MDA-MB-231 and BT549, and found that it hindered cell proliferation, increased apoptosis, and repressed cell invasion and migration. BRCA1 exerts multiple functions and is closely related to the occurrence and development of breast cancer. Interestingly, the mRNA and protein expression of BRCA1 increased after liquiritigenin administration. Liquiritigenin also upregulated two downstream genes of BRCA1 (p21 and DNA-damage-inducible 45 alpha), decreased cellular DNA methyltransferase (DNMT) activity, and reduced BRCA1 promoter methylation. Thus, liquiritigenin may be a promising candidate for the treatment of TNBC due to its inhibition of DNMT activity and upregulation of BRCA1.

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Liquiritigenin Inhibits Colorectal Cancer Proliferation, Invasion, and Epithelial-to-Mesenchymal Transition by Decreasing Expression of Runt-Related Transcription Factor 2

Cited by 35 publications

References 29 publications

Flavonoids in Cancer Metastasis

Flavonoids in Cancer Metastasis

Isoliquiritin Apioside Suppresses in vitro Invasiveness and Angiogenesis of Cancer Cells and Endothelial Cells

Liquiritigenin decreases tumorigenesis by inhibiting DNMT activity and increasing BRCA1 transcriptional activity in triple-negative breast cancer

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