DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) is a drug from the beta-carboline family. doi: 10.1038/jid.2012.63, Halaban, R., Zhang, W., Bacchiocchi, A., Cheng, E., Parisi, F., Ariyan, S., et al. (2014). The expression levels of each gene were normalized to β-actin expression levels and adjusted to the levels in untreated tumor cells (medium). It has lancet-shaped leaves, purple-blue flowers, and black-brown, egg-shaped nutlets. Data in panel (B) are mean ± SD from three independent experiments with similar results. We then investigated whether baicalein and baicalin have inhibitory effects on the other key biological behaviors of melanoma cells, including colony formation, migration and adhesion capacities. Tumor volume was calculated on the basis of two-dimensional measurements. These results clearly suggest that both baicalein and baicalin strongly suppress melanoma cell proliferation and growth. Our results clearly showed that both human and mouse melanoma cells had high glucose uptake abilities. Figure 8. Recent studies suggest that many natural products have been developed into promising drugs and applied into clinical trials for various disease treatments including cancers (Cragg et al., 2009; Cragg and Newman, 2013; Stover et al., 2014). is that baicalein is (organic compound) 5,6,7-trihydroxyflavone, a flavone originally isolated from the roots of scutellaria baicalensis that acts as a lipoxygenase inhibitor and anti-inflammatory agent while baicalin is (organic compound) a flavone, the glucuronide of baicalein, found in scutellaria baicalensis and related plants and used in herbal medicine. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001, compared with the PBS treatment control group using unpaired t-test. A standardized and purified extract of S. baicalensis containing baicalein, oroxylin A, and wogonin exerted anti … Our previously studies have shown that baicalein and baicalin can induce colon cancer cell apoptosis and senescence (Dou et al., 2018; Wang et al., 2018). TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. ***p < 0.001, compared with the PBS control treatment mice using unpaired t-test. Clin. Furthermore, the molecular mechanism by which the two compounds inhibit cancer is still unclear. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Baicalin and its aglycon baicalein are flavonoids extracted from Scutellaria baicalensis, an important traditional Chinese herb. Data shown are mean ± SD from three independent experiments with similar results. 18, 1503–1510. However, how and whether baicalein and baicalin inhibit colon cancer is unclear. Liu Y, Yang S, Wang K, Lu J, Bao X, Wang R, Qiu Y, Wang T, Yu H. Cell Prolif. In our effort to identify how baicalein and baicalin molecularly inhibit melanoma growth, we demonstrated that baicalein and baicalin can metabolically reprogram melanoma cells via inhibition of glucose uptake and downregulation of the key enzymes in glucose transport and glycolysis in tumor cells. Baicalin (14) and its aglycone baicalein (15) are flavones that exhibit a variety of biological effects, including anti-inflammatory and anticancer properties. Cancer 11, 325–337. Potential therapeutic effects of baicalein, baicalin, and wogonin in ocular disorders. ***p < 0.001, compared with the PBS treatment control mice using unpaired t-test. BioPure Baikalin Powder is a powdered extract from the root of Scutellaria baicalensis, also known as Chinese Skullcap, Huang-Qin, or Baikal Skullcap. All animal studies have been approved by the Institutional Animal Care Committee. Although many inhibitors have been developed to target the mutations and/or activated signaling pathways, the overall effects of the inhibitors against melanoma are limited in certain types of clinical patients (Brose et al., 2002; Thumar et al., 2014). Med. In our current studies, we utilized different types of melanoma cell lines with/without N-RAS and B-RAF mutations, including Mel586, SK-MEL-2 (wild type B-Raf and mutant N-RAS), A375 (B-RAF V600E and wild type N-RAS), as well as mouse B16F0 melanoma cell line. (2012). MATRIGEL® basement membrane matrix was obtained from Becton Dickinson (Bedford, MA). Molecular Weight 446.36 . A., Bassett, R. L. Jr., Ng, C. S., Curry, J. L., Joseph, R. W., Alvarado, G. C., et al. *p < 0.05, **p < 0.01, and ***p < 0.001, compared with the medium control group. Baicalin has attracted increasing scientific attention because of its various pharmacological activities such as antioxidant, antitumor, anti-inflammatory and hepatoprotective effects [ 4 , 5 ]. MAPK p38 and ERK1/2 signaling pathways involve colon cancer cell apoptosis and senescence…, Figure 7. Baicalein and baicalin strongly inhibit melanoma cell behaviors and functions, including tumor cell growth and proliferation, as well as colony formation and migration. (2018). Baicalein, however, appears to be one of the most powerful and widely studied flavones. Helicobacter pylori infection is associated with chronic gastritis, peptic ulcers, and gastric cancer. PubMed:Baicalin induces differential expression of cytochrome C oxidase in human lung H441 cell. doi: 10.1021/cr900019j, Cragg, G. M., and Newman, D. J. Biochim. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. We show here that low micromolar concentrations of baicalein, and especially its oxidized forms, inhibit the formation of alpha-synuclein fibrils. 2020 Oct;53(10):e12894. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Epub 2015 Sep 18. Inhibition of Autophagy Amplifies Baicalein-Induced Apoptosis in Human Colorectal Cancer. Cancer Ther. (A,B) Increased senescent cell populations were induced in human and mouse melanoma cells after treatments with baicalein and baicalin. Sferrazza G, Corti M, Brusotti G, Pierimarchi P, Temporini C, Serafino A, Calleri E. Acta Pharm Sin B. Aryal, P., Kim, K., Park, P. H., Ham, S., Cho, J., and Song, K. (2014). *p < 0.05, **p < 0.01, and ***p < 0.001, compared with the medium control group. Pharmacol. In addition, we activated HIF1α function with the specific pharmacological activator dimethyloxalylglycine (DMOG) and then evaluated glycolysis inhibition and cell senescence induction mediated by baicalein and baicalin (Zhdanov et al., 2015; Cosin-Roger et al., 2017). Potential Treatment of Breast and Lung Cancer Using. Data from this study suggested that baicalein is a potent anticancer metabolite derived from S. baicalensis. Noh K, Kang Y, Nepal MR, Jeong KS, Oh DG, Kang MJ, Lee S, Kang W, Jeong HG, Jeong TC. We have demonstrated that MAPK ERK and p38 signaling pathways are involved in baicalein and baicalin-induced apoptosis and senescence in colon cancer (Dou et al., 2018). Importantly, our current studies further identified the metabolic control as a novel molecular mechanism responsible for the tumor suppression mediated by baicalein and baicalin. Cancer 118, 4014–4023. Pharmacol. ∗∗∗p < 0.001, compared with the medium control group. Received: 29 May 2020; Accepted: 04 August 2020;Published: 25 August 2020. Scutellaria ba … Acta 1847, 1254–1266. To further test the possibility that baicalein and baicalin-mediated suppression of melanoma cells involves the mTORC1–HIF1α signaling pathway regulation, we also determined HIF1α protein and mRNA expression in both human and mouse melanoma cells treated with or without the two compounds using the flow cytometry and Real-time PCR analyses. Baicalein- and baicalin-mediated inhibition of colon cancer cell growth and proliferation is due…, Figure 5. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. PLoS One 2:e236. Baicalin appears to involve intestinal microflora for its metabolism into baicalein, the most active metabolite of baicalin. Warburg, O. Our in silico interaction assays predicted that both compounds exhibited the strongest binding affinities towards ZIKV NS5, while the virus envelope glycoprotein was the least likely target protein. Rep. 4:5452. Mechanistically, we identify that the suppression of baicalein and baicalin on melanoma cells is due to inhibition of tumor cell glucose uptake and metabolism by affecting the mTOR-HIF-1α signaling pathway. 200–500 per well of melanoma cells pre-treated with the indicated concentrations of baicalein or baicalin, were seeded in 6-well plates for culture, and cell colonies counted after 10–14 days of culture. FIGURE S3 | Baicalein and baicalin treatments down-regulate gene expression levels of key glycolytic enzymes in B16F0 tumor cells in vivo. (2011). eCollection 2020. 126, 844–852. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error, Three colon cancer cell lines (HCT116, SW480 and HT29) were cultured at a started number of 2 × 10. These are significantly obstacles for a target therapy against melanoma. Baicalin, baicalein and wogonin inhibits high glucose-induced vascular inflammation in vitro and in vivo. doi: 10.1016/j.jep.2015.11.018, Johnson, J. J. Cragg, G. M., Grothaus, P. G., and Newman, D. J. Proc. doi: 10.1016/j.taap.2011.07.008, Chung, H., Choi, H. S., Seo, E. K., Kang, D. H., and Oh, E. S. (2015). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Therefore, we measured apoptosis and cell death in melanoma cell lines treated by both baicalein and baicalin. Our previous studies have further demonstrated that baicalein and baicalin can suppress colon cancer cell proliferation and growth in vitro and in vivo (Dou et al., 2018; Wang et al., 2018). Figure 2. (2010). 8:836. doi: 10.3389/fcell.2020.00836. Metabolic reprogramming of immune cells in cancer progression. NCI CPTC Antibody Characterization Program. Panel (I) is the summary of mean ± SD of cleaved caspase-3+ cell fractions per high microscope field (×400) in the tumor tissues from four mice of each group. Nature 552, 368–373. Baicalin is a glycosylated compound derived from baicalein, and it has a functional group of D-glucopyranosiduronic acid on site 7 of baicalein (Figure 1), so that it will exhibit more biological function. Atlanta, GA: American Cancer Society. *Correspondence: Huaxi Xu, xuhx@ujs.edu.cn; Guangyong Peng, guangyong.peng@health.slu.edu, †Present address: Bo Peng, Washington University, St. Louis, MO, United States; Yash Nayak, Washington University, St. Louis, MO, United States, Front. Biol. The expression levels of each gene were normalized to β-actin expression levels and adjusted to the levels in untreated tumor cells (medium). The suppressive effects are mechanistically due to the induction of colon cancer cell apoptosis and senescence mediated by baicalein and baicalin, respectively. Baicalein and baicalin are active components of the Scutellaria baicalensis Georgi and both have broad anti-tumor activity. Oncotarget 6, 7880–7898. TLR8-mediated metabolic control of human treg function: a mechanistic target for cancer immunotherapy. Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase. A375 and SK-MEL-2 were maintained in DMEM medium containing 10% FBS. We further identified four baicalein analogue compounds from other herbs that inhibit SARS-CoV-2 3CLpro activity at microM concentration. 62, 6997–7000. Melanoma cells were pretreated with different concentrations of baicalein and baicalin for 72 h. Treated and untreated melanoma cells were cultured in the glucose-free medium for 30 min, and followed addition of 2-NBDG (100 μM) for 20 min and analyzed with a FACSCalibur flow cytometer (BD Bioscience). 2013;63:11–30. Scutellaria ba … Res. The present study demonstrated that the Scutellariae radix compounds baicalein and baicalin may serve as drugs for the treatment of autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease. Tumor growth was evaluated. In addition, the currently developed inhibitors, such as PLX4720 and PLX4032, show limitations as they could not cure melanoma with both N-RAS and B-RAF mutations (Halaban et al., 2010; Kaplan et al., 2012). Baicalein is one of the active i Baicalein exhibited its highest potency during intracellular ZIKV replication, whereas baicalin was most effective against virus entry. In addition, both baicalein and baicalin inhibited LDHα expression in Mel586, A375, and B16F0 melanoma cells, and ENO1 expression in SK-MEL-2 and A375 cells, as well as partially suppressed PKM2 expression in SK-MEL-2, A375, and B16F0 tumor cells (Supplementary Figure S2). (2010). (2015). Colon cancer chemopreventive effects of baicalein, an active enteric microbiome metabolite from baicalin. Consistent with the results from Retro-Rheb transfection, activation of HIF1α signaling with DMOG in tumor cells markedly blocked the inhibition of gene expression of glucose transporters and glycolytic enzymes and prevented induction of senescence in melanoma cells mediated by baicalein and baicalin (Figures 7A,B). Baicalein is a flavonoid with antioxidant properties; upon oxidation, it forms several products including quinones. Baicalin also demonstrated the most effective inhibition activity when compared with baicalein and wogonin.13 Wogonin, baicalein, and baicalin all have been found to influence some anti-inflammatory pathways via certain proteins, antigens, and enzymes.14, 15, 16. We observed that the numbers and sizes of tumor cell colonies were significantly decreased in SK-MEL-2 and A375 tumor cells after treatment with baicalein or baicalin (Figures 2A,B). 9, 6483–6488. Interestingly, treatments with baicalein and baicalin also induced some necrotic cell populations in SK-MEL-2 and B16F0 tumor cells (Figure 3A). Siegel RL, Miller KD, Jemal A. Furthermore, mTOR signaling activation markedly prevented the baicalein and baicalin-induced senescence in both human and mouse melanoma cells (Figure 7B). Med. Cell Dev. Commun. Other flavones, such as baicalin, wogonin and apigenin, are also often distilled from these plants. CONFLICTS OF INTEREST The authors declare no competing financial interests. doi: 10.3892/ijo.2015.3173. We demonstrated that baicalein and baicalin can significantly inhibit both human and mouse melanoma cell growth and proliferation, suppress tumor cell colony formation and migration, as well as induce apoptosis and senescence in melanoma cells. BQ Li et al., “The flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines”, Immunopharmacology. Biochim. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. At the end of experiments, tumor issues were grinded and total RNA was extracted. Med. 2014;20:9775–827. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. We then determined the effect on key glycolytic enzymes in tumor cells using real-time quantitative PCR analyses (Li et al., 2019). (2016). Baicalin has been shown to offer various pharmacological effects in research, including protection against free radical damage, inflammation modulating, neuroprotective, and immune system support. In addition, we demonstrated that baicalein and baicalin can suppress tumorigenesis and tumor growth in vivo in the melanoma model. In vitro antiproliferative effects on CRC cells were verified using an in vivo xenograft nude mouse model. Tumor cell growth and proliferation were further determined using cell growth curve and [3H]-thymidine incorporation assays. (2013). The expression of mTOR-HIF-1α signaling markers on tumor cells were determined by FACS analysis after staining with anti-human specific antibodies, including anti-phosphorylated mTOR (1:500), p70S6K (1:500), and 4E-BP1 (1:1000), as well as anti-HIF-1α (1:1000) and then secondary anti-rabbit antibody conjugated with either PE or FITC. Baicalein and baicalin are active components of Scutellaria baicalensis Georgi. U.S.A. 108, 4129–4134. 23, 190–200. mTOR signaling pathway plays a central role in metabolic reprogramming of tumor cell growth and proliferation (Sun et al., 2011; Chen et al., 2015). doi: 10.1016/j.ccr.2012.02.014, Xiao, J. R., Do, C. W., and To, C. H. (2014). The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2020.00836/full#supplementary-material. LH, BP, YN, CW, FS, and XL performed the experiments. Furthermore, N-RAS and B-RAF mutations in melanoma cells increase the difficulties for clinical treatment in patients. J. Med. (2015). Though it has broad therapeutic capability, the bioavailability is limited due to its poor solubility. Nat. J. Exp. Acta 1813, 1465–1474. Two hundred to five hundred per well of melanoma cells treated with different concentrations of baicalein or baicalin, were seeded in 6-well plates and cultured for 10–14 days. Am J Chin Med. (2018). Baicalin is calming. Figure 4. Results shown in the histogram (B) are summaries of mean ± SD from three independent experiments. 109, 3012–3043. MDL number MFCD00134418. Baicalin, along with its aglycone baicalein, is a positive allosteric modulator of the benzodiazepine site and/or a non-benzodiazepine site of the GABA A receptor. mTORC1-dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. To further investigate the causative role of glucose metabolism inhibition in cell senescence and suppression of melanoma cells mediated by these two compounds, we determined whether we can prevent tumor cell senescence mediated by baicalein and baicalin if we promote glucose mentalism through overexpression of Glut1 gene in the melanoma cells. (2012). Furthermore, treatments with baicalein and baicalin significantly inhibited HIF1α expression in all melanoma cells, suggesting down-regulation of HIF1α pathway in melanoma cells induced by the two compounds (Figures 6B,C). 100, 296–308. We observed significantly decreased gene expression levels of glucose transporters Glut1 and Glut3, as well as the key glycolytic enzymes in tumor tissues treated with baicalein or baicalin, further suggesting inhibition of glycolysis in tumor cells (Supplementary Figure S3). The flavonoid compounds baicalin and baicalein found in many medicinal plants exhibit an anti‐inflammatory effect. NIH Melanoma cells were treated with or without indicated concentrations of baicalein and baicalin for 72 h. Total RNA was isolated from the tumor cells and analyzed by real-time PCR. Data shown in different melanoma cells are mean ± SD from three independent experiments. Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. These studies clearly indicate that baicalein and baicalin can control tumor growth and development metabolically and have great potential as novel and universal drugs for melanoma therapy. LH, HX, and GP designed research, analyzed the data, prepared figures, and wrote the manuscript. Baicalein begins life as baicalin. HPLC analysis demonstrated that baicalin was dominant in the MeOH extract; baicalein and chrysin were rich in the EtOAc and chloroform extracts. J. Exp. Cancer Cell 21, 297–308. (A) Suppression of phosphorylation and subsequent activation of mTOR signaling in melanoma cells treated with baicalein and baicalin. Mechanistic studies further demonstrated that baicalein and baicalin-mediated suppression of melanoma growth and development is through the inhibition of glucose metabolism in tumor cells, promoting tumor cell … Nature 464, 427–430. Finally, optimization of malonyl-CoA availability further increased the production of baicalein to 23.6 mg/L and scutellarein to 106.5 mg/L in a flask culture. The closure was estimated as the wounded area relative to the initial area (Liu et al., 2015; Dou et al., 2018; Wang et al., 2018). is that baicalein is (organic compound) 5,6,7-trihydroxyflavone, a flavone originally isolated from the roots of scutellaria baicalensis that acts as a lipoxygenase inhibitor and anti-inflammatory agent while baicalin is (organic compound) a flavone, the glucuronide of baicalein, found in scutellaria baicalensis and related plants and used in herbal medicine. doi: 10.1073/pnas.1014769108. Eur J Med Chem. Cancer statistics, 2012. Baicalin is a flavone glycoside, the glucuronide of baicalein, which is obtained through the binding of glucuronic acid to baicalein. Thumar, J., Shahbazian, D., Aziz, S. A., Jilaveanu, L. B., and Kluger, H. M. (2014). However, how and whether baicalein and baicalin inhibit colon cancer is unclear. Scutellaria baicalensis Georgi is one of the most important traditional Chinese medicines, which is widely used for the disease treatments. #p < 0.05, ##p < 0.01, and ###p < 0.001, compared with the respective baicalein or baicalin treatment group. (2014). The sections were further blocked with 3.7% formaldehyde for 30 min and added the primary antibodies, including anti-Ki-67 (#9129, Cell Signaling Technology), anti-cleaved caspase-3 (#9664, Cell Signaling Technology) at diluted concentrations of 1:50 and 1:400, respectively, under 4°C overnight. Lu Y, Joerger R, Wu C. Study of the chemical composition and antimicrobial activities of ethanolic extracts from roots of Scutellaria baicalensis Georgi. Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Clin. Baicalin treatment inhibits the increased expression of the proinflammatory cytokines TLR2/4, MyD88, p-NF-κB, and p- IκB, as well as increase the expression of IκB protein, an NF-κB inhibitor, with the degree of inhibition positively related to the dosage of Baicalin. |, https://www.frontiersin.org/articles/10.3389/fcell.2020.00836/full#supplementary-material, Creative Commons Attribution License (CC BY). (1956). (2011). 176, 475–484. (2018). Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. The plant is found in Japan, China, Korea, Mongolia, and Russia 1 and thrives on … J. Oncol. Yu, C., Zhang, Z., Zhang, H., Zhen, Z., Calway, T., Wang, Y., et al. (2007). Adherent cells were counted and averaged in 10 fields at high (×400) magnification with a microscope. Baicalein and baicalin treatments down-regulate glucose uptake and glycolysis in melanoma cells. Baicalein and baicalin inhibit colon cancer using two distinct fashions of apoptosis and senescence. For single comparison between two groups, paired Student’s t-test was used. We detected the gene expression of the key enzymes involved in glycolysis in tumor tissues obtained from different groups. JAMA Oncol. This herb is in the Lamiaceae (mint) family and gets its name from its blue to purplish-pink flowers that have a shape resembling a medieval knight’s helmet. We have recently demonstrated that baicalein and baicalin could inhibit human colon cancer cell growth and proliferation in vitro and in vivo (Dou et al., 2018; Wang et al., 2018). doi: 10.1016/j.ejmech.2016.11.058, Gowrishankar, K., Snoyman, S., Pupo, G. M., Becker, T. M., Kefford, R. F., and Rizos, H. (2012). Role of Intestinal Microbiota in Baicalin-Induced Drug Interaction and Its Pharmacokinetics. Cell colonies were fixed with 4% formaldehyde, stained with 0.5% crystal violet for 15 min at room temperature, washed for several times and then counted under a microscope, as we described previously (Liu et al., 2015; Dou et al., 2018; Wang et al., 2018). Commun. 30, 605–614. LiftMode Baicalein Powder Supplement - Chinese Skullcap Herb for Relaxation, Stress Relief & Overall Health | Enhances Cognition & Learning | Vegetarian, Non-GMO, Gluten Free - 20 Grams (67 Servings) 4.3 out of 5 stars 4. PubMed:Effects of scutellariae radix extract and its components (baicalein, baicalin, and wogonin) on the experimental elevation of aqueous flare in pigmented rabbits. The basic structure of baicalin consists of benzopyran with three hydroxyl groups at site 5, 6, and 7 and a phenyl group at the other side of the benzopyran (site 2). Both compounds can inhibit the proliferation, migration, adhesion and invasive properties of tumor cells, and induce tumor cell cycle arrest (Chao et al., 2007; Chiu et al., 2011; Takahashi et al., 2011; Aryal et al., 2014; Wang et al., 2015; Gong et al., 2017). The anti-tumor effects mediated by baicalein and baicalin are independent of N-RAS and B-RAF mutation statuses in melanoma cells. Cancer Res. doi: 10.1038/nm.2941. Baicalein and baicalin inhibit tumor growth and tumorigenesis of melanoma in vivo. Li, L., Liu, X., Sanders, K. L., Edwards, J. L., Ye, J., Si, F., et al. Baicalein inhibits the migration and invasive properties of human hepatoma cells. In addition, baicalein has stronger inhibitory activity on melanoma cell growth and proliferation than that of baicalin. 159, 3269–3278. Melanoma, a type of skin cancer, is one of the deadly cancers in the world. (2012). *p < 0.05, **p < 0.01, and ***p < 0.001, compared with the medium only group.
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