PMID: 

Sci Rep. 2015 May 18 ;5:10336. Epub 2015 May 18. PMID: 25981581

Abstract Title: 

Licochalcone A-induced human gastric cancer BGC-823 cells apoptosis by regulating ROS-mediated MAPKs and PI3K/AKT signaling pathways.

Abstract: 

Both phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK) signaling cascades play an important role in cell proliferation, survival, angiogenesis, and metastasis of tumor cells. In the present report, we investigated the effects of licochalcone A (LA), a flavonoid extracted from licorice root, on the PI3K/AKT/mTOR and MAPK activation pathways in human gastric cancer BGC-823 cells. LA increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding and activation of caspase-3, and cleavage of poly-ADP-ribose polymerase (PARP). Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented LA-induced apoptosis. Interestingly, we also observed that LA caused the activation of ERK, JNK, and p38 MAPK in BGC-823 cells. The antitumour activity of LA-treated BGC-823 cells was significantly distinct in KM mice in vivo. All the findings from our study suggest that LA can interfere with MAPK signaling cascades, initiate ROS generation, induce oxidative stress and consequently cause BGC cell apoptosis.

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PMID: 

Oncotarget. 2015 Oct 6 ;6(30):28851-66. PMID: 26311737

Abstract Title: 

Licochalcone A induces autophagy through PI3K/Akt/mTOR inactivation and autophagy suppression enhances Licochalcone A-induced apoptosis of human cervical cancer cells.

Abstract: 

The use of dietary bioactive compounds in chemoprevention can potentially reverse, suppress, or even prevent cancer progression. However, the effects of licochalcone A (LicA) on apoptosis and autophagy in cervical cancer cells have not yet been clearly elucidated. In this study, LicA treatment was found to significantly induce the apoptotic and autophagic capacities of cervical cancer cells in vitro and in vivo. MTT assay results showed dose- and time-dependent cytotoxicity in four cervical cancer cell lines treated with LicA. We found that LicA induced mitochondria-dependent apoptosis in SiHa cells, with decreasing Bcl-2 expression. LicA also induced autophagy effects were examined by identifying accumulation of Atg5, Atg7, Atg12 and microtubule-associated protein 1 light chain 3 (LC3)-II. Treatment with autophagy-specific inhibitors (3-methyladenine and bafilomycin A1) enhanced LicA-induced apoptosis. In addition, we suggested the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of mTOR pathway by LicA. Furthermore, the inhibition of PI3K/Akt by LY294002/si-Akt or of mTOR by rapamycin augmented LicA-induced apoptosis and autophagy. Finally, the in vivo mice bearing a SiHa xenograft, LicA dosed at 10 or 20 mg/kg significantly inhibited tumor growth. Our findings demonstrate the chemotherapeutic potential of LicA for treatment of human cervical cancer.

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PMID: 

Inflammation. 2016 Apr ;39(2):569-74. PMID: 26552405

Abstract Title: 

Licochalcone A Attenuates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting NF-κB Activation.

Abstract: 

Licochalcone A (Lico A), a flavonoid found in licorice root (Glycyrrhiza glabra), has been reported to have anti-inflammatory activity. However, the protective effects of Lico A on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) remains unclear. In this study, using a mouse model of LPS-induced AKI, we investigated the protective effects and mechanism of Lico A on LPS-induced AKI in mice. LPS-induced kidney injury was assessed by detecting kidney histological study, blood urea nitrogen (BUN), and creatinine levels. The production of inflammatory cytokines TNF-α, IL-6, and IL-1β in serum and kidney tissues was detected by ELISA. The activation of NF-κB was measured by western blot analysis. Our results showed that Lico A dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. Lico A also suppressed LPS-induced TNF-α, IL-6, and IL-1β production both in serum and kidney tissues. Furthermore, our results showed that Lico A significantly inhibited LPS-induced NF-κB activation. In conclusion, our results suggest that Lico A has protective effects against LPS-induced AKI and Lico A exhibits its anti-inflammatory effects through inhibiting LPS-induced NF-κB activation.

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PMID: 

Planta Med. 2019 Nov ;85(16):1203-1215. Epub 2019 Sep 20. PMID: 31539918

Abstract Title: 

Cardiovascular Protective Effects of Centella asiatica and Its Triterpenes: A Review.

Abstract: 

, a triterpene-rich medicinal herb, is traditionally used to treat various types of diseases including neurological, dermatological, and metabolic diseases. A few articles have previously reviewed a broad range of pharmacological activities of, but none of these reviews focuses on the use ofin cardiovascular diseases. This review aims to summarize recent findings on protective effects ofand its active constituents (asiatic acid, asiaticoside, madecassic acid, and madecassoside) in cardiovascular diseases. In addition, their beneficial effects on conditions associated with cardiovascular diseases were also reviewed. Articles were retrieved from electronic databases such as PubMed and Google Scholar using keywords",""asiatic acid,""asiaticoside,""madecassic acid,"and"madecassoside."The articles published between 2004 and 2018 that are related to the aforementioned topics were selected. A few clinical studies published beyond this period were also included. The results showed thatand its active compounds possess potential therapeutic effects in cardiovascular diseases and cardiovascular disease-related conditions, as evidenced by numerous, and clinical studies.and its triterpenes have been reported to exhibit cardioprotective, anti-atherosclerotic, antihypertensive, antihyperlipidemic, antidiabetic, antioxidant, and anti-inflammatory activities. In conclusion, more clinical and pharmacokinetic studies are needed to support the use ofand its triterpenes as therapeutic agents for cardiovascular diseases. Besides, elucidation of the molecular pathways modulated byand its active constituents will help to understand the mechanisms underlying the cardioprotective action of.

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PMID: 

Mol Med Rep. 2016 Jul ;14(1):911-9. Epub 2016 May 24. PMID: 27221781

Abstract Title: 

Licochalcone A induces T24 bladder cancer cell apoptosis by increasing intracellular calcium levels.

Abstract: 

Licochalcone A (LCA) has been reported to significantly inhibit cell proliferation, increase reactive oxygen species (ROS) levels, and induce apoptosis of T24 human bladder cancer cells via mitochondria and endoplasmic reticulum (ER) stress-triggered signaling pathways. Based on these findings, the present study aimed to investigate the mechanisms by which LCA induces apoptosis of T24 cells. Cultured T24 cells were treated with LCA, and cell viability was measured using the sulforhodamine B assay. Apoptosis was detected by flow cytometry with Annexin V/propidium iodide staining, and by fluorescent microscopy with Hoechst 33258 staining. The levels of intracellular free calcium ions were determined using Fluo-3 AM dye marker. Intracellular ROS levels were assessed using the 2',7'-dichlorodihydrofluorescein diacetate probe assay. The mitochondrial membrane potential was measured using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl benzimidazole carbocyanine iodide. Furthermore, the mRNA expression levels of B‑cell lymphoma (Bcl)‑extra large, Bcl‑2‑associated X protein, Bcl‑2‑interacting mediator of cell death, apoptotic protease activating factor‑1 (Apaf‑1), calpain 2, cysteinyl aspartate specific proteinase (caspase)‑3, caspase‑4 and caspase‑9 were determined using reverse transcription semiquantitative and quantitative polymerase chain reaction analyses. Treatment with LCA inhibited proliferation and induced apoptosis of T24 cells, and increased intracellular Ca2+levels and ROS production. Furthermore, LCA induced mitochondrial dysfunction, decreased mitochondrial membrane potential, and increased the mRNA expression levels of Apaf‑1, caspase‑9 and caspase‑3. Exposure of T24 cells to LCA also triggered calpain 2 and caspase‑4 activation, resultingin apoptosis. These findings indicated that LCA increased intracellular Ca2+ levels, which may be associated with mitochondrial dysfunction. In addition, the ER stress pathway may be considered an important mechanism by which LCA induces apoptosis of T24 bladder cancer cells.

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PMID: 

Biomed Pharmacother. 2017 Jan ;85:425-433. Epub 2016 Nov 27. PMID: 27903423

Abstract Title: 

Cytotoxicity of trans-chalcone and licochalcone A against breast cancer cells is due to apoptosis induction and cell cycle arrest.

Abstract: 

Chalcones are precursors of flavonoids that exhibit structural heterogeneity and potential antitumor activity. The objective of this study was to characterize the cytotoxicity of trans-chalcone and licochalcone A (LicoA) against a breast cancer cell line (MCF-7) and normal murine fibroblasts (3T3). Also the mechanisms of the anti-cancer activity of these two compounds were studied. The alkaline comet assay revealed dose-dependent genotoxicity, which was more responsive against the tumor cell line, compared to the 3T3 mouse fibroblast cell line. Flow cytometry showed that the two chalcones caused the cell cycle arrest in the G1 phase and induced apoptosis in MCF-7 cells. Using PCR Array, we found that trans-chalcone and LicoA trigger apoptosis mediated by the intrinsic pathway as demonstrated by the inhibition of Bcl-2 and induction of Bax. In western blot assay, the two chalcones reduced the expression of cell death-related proteins such as Bcl-2 and cyclin D1 and promoted the cleavage of PARP. However, only trans-chalcone induced the expression of the CIDEA gene and protein in these two experiments. Furthermore, transient transfections of MCF-7 using a construction of a promoter-luciferase vector showed that trans-chalcone induced the expression of the CIDEA promoter activity in 24 and 48h. In conclusion, the results showed that trans-chalcone promoted high induction of the CIDEA promoter gene and protein, which is related to DNA fragmentation during apoptosis.

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PMID: 

J Ethnopharmacol. 2017 Feb 23 ;198:331-337. Epub 2017 Jan 19. PMID: 28111219

Abstract Title: 

Antioxidative and anticancer properties of Licochalcone A from licorice.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: Licochalcone A (LCA) is a characteristic chalcone that is found in licorice, which is a traditional medicinal plant. In traditional medicine, LCA possesses many potential biological activities, including anti-parasitic, anti-inflammatory and antitumor activities.AIM OF THE STUDY: To determine the antioxidant activity of LCA and, on this basis, to investigate the role of its anticancer activity.MATERIALS AND METHODS: To validate the antioxidant activity of LCA, the proteins SOD, CAT and GPx1 were analyzed using western blotting and cellular antioxidant activity (CAA) assays. Oxidative free radicals are associated with cancer cells. Therefore, the anticancer activity of LCA was also evaluated. To assess the anticancer activity, cell viability assays were performed and apoptosis was evaluated. In addition, MAPK-related proteins were analyzed using western blotting.RESULTS: The experimental data showed that the ECof LCA is 58.79±0.05μg/mL and 46.29±0.05μg/mL under the two conditions tested, with or without PBS. In addition, LCA at a concentration of approximately 2-8μg/mL can induce the expression of SOD, CAT and GPx1 proteins. Further, LCA inhibits the growth of HepG2 cells through cell proliferation arrest and the subsequent induction of apoptosis, and LCA attenuated the p38/JNK/ERK signaling pathway in a dose-dependent manner.CONCLUSION: The results showed that LCA suppresses the oxidation of cells and markedly inhibits the proliferation of cancer cells. These findings confirm the traditional use of LCA in folk medicine.

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PMID: 

Oncol Lett. 2017 Mar ;13(3):1695-1701. Epub 2017 Jan 18. PMID: 28454311

Abstract Title: 

Antitumor effects and the underlying mechanism of licochalcone A combined with 5-fluorouracil in gastric cancer cells.

Abstract: 

Licochalcone A (LCA) is a flavonoid extracted from licorice root that has antiparasitic, antibacterial and antitumor properties. Previous studies have revealed that LCA may be a novel treatment for gastric cancer. The present study further assessed the potential antitumor effects of LCA alone or in combination with 5-fluorouracil (5-FU), and the underlying mechanisms responsible for those effects in gastric cancer cells. The effects of LCA alone or in combination with 5-FU on SGC7901 and MKN-45 gastric cancer cell lines were studied using Cell Counting Kit-8, cell cycle, apoptosis and western blot analyses of cell check points and apoptosis-associated proteins. The results revealed that LCA inhibited cell proliferation, blocked cell cycle progression at the G/M transition and induced apoptosis. Western blot analysis demonstrated that LCA treatment increased the levels of tumor proteins 21 and 27, as well as mouse double minute 2 homolog in gastric cancer cells. In addition, LCA treatment increased the expression levels of Bax, cleaved-poly ADP ribose polymerase, tumor protein 53 and caspase 3, and decreased the expression levels of Bcl-2. Therefore, the present study demonstrated that LCA alone or in combination with 5-FU may have significant anticancer effects on gastric cancer cells, and may be a novel therapeutic for the treatment of gastric cancer in the future.

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PMID: 

J Cell Biochem. 2017 12 ;118(12):4652-4663. Epub 2017 Jun 12. PMID: 28498645

Abstract Title: 

Licochalcone A Suppresses Specificity Protein 1 as a Novel Target in Human Breast Cancer Cells.

Abstract: 

Licochalcone A (LCA), isolated from the root of Glycyrrhiza inflata, are known to have medicinal effect such as anti-oxidant, anti-bacterial, anti-viral, and anti-cancer. Though, as a pharmacological mechanism regulator, anti-cancer studies on LCA were not investigated in human breast cancer. We investigated the anti-proliferative and apoptotic effect of LCA in human breast cancer cells MCF-7 and MDA-MB-231 through MTS assay, PI staining, Annexin-V/7-AAD assay, mitochondrial membrane potential assay, multi-caspase assay, RT-PCR, Western blot analysis, and anchorage-independent cell transformation assay. Our results showed the little difference between two cells, as MCF-7 cell is both estrogen/progesterone receptor positive, there were only effect on Sp1 protein level, but not in mRNA level. Adversely, estrogen/progesterone/human epidermal growth factor receptor 2 triple negative, MDA-MB-231 showed decreased Sp1 mRNA, and protein levels. To confirm the participation of Sp1 in breast cancer cell viability, siRNA techniques were introduced. Both cells showed dysfunction of mitochondrial membrane potential and mitochondrial ROS production, which reflects it passed intracellular mitochondrial apoptosis pathway. Additionally, LCA showed the anti-proliferative and apoptotic effect in breast cancer cells through regulating Sp1 and apoptosis-related proteins in a dose- and a time-dependent manner. Consequently, LCA might be a potential anti-breast cancer drug substitute. J. Cell. Biochem. 118: 4652-4663, 2017.© 2017 Wiley Periodicals, Inc.

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PMID: 

FEBS Open Bio. 2017 06 ;7(6):835-844. Epub 2017 May 8. PMID: 28593138

Abstract Title: 

Licochalcone A specifically induces cell death in glioma stem cells via mitochondrial dysfunction.

Abstract: 

Glioblastoma multiforme is the most malignant primary intrinsic brain tumor. Glioma stem cells (GSCs) are associated with chemoradiotherapy resistance and the recurrence of glioblastomas after conventional therapy. The targeting of GSCs is potentially an effective treatment for the long-term survival of glioblastoma patients. Licochalcone A, a natural chalconoid from licorice root, exerts anticancer effects; however, its effect on GSCs remains unknown. We found that Licochalcone A induced massive caspase-dependent death in GSCs but not in differentiated GSCs nor normal somatic and neural stem cells. Prior to cell death, Licochalcone A caused mitochondrial fragmentation and reduced the membrane potential and ATP production in GSCs. Thus, Licochalcone A induces mitochondrial dysfunction and shows promise as an anticancer stem cell drug.

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