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http://dx.doi.org/10.14374/HFS.2020.28.1.63

18α-Glycyrrhetinic acid induces apoptosis of AGS human gastric cancer cells  

Kim, Jeong Nam (Division of Longevity and Biofunctional Medicine School of Korean Medicine, Pusan National University)
Kim, Byung Joo (Division of Longevity and Biofunctional Medicine School of Korean Medicine, Pusan National University)
Publication Information
Herbal Formula Science / v.28, no.1, 2020 , pp. 63-70 More about this Journal
Abstract
Objectives : The purpose of this study was to investigate the anti-cancer effects of 18α-Glycyrrhetinic acid (18α-GA), a hydrolyzed metabolite of glycyrrhizin, in AGS human gastric adenocarcinoma cells. Methods : We used human gastric adenocarcinoma cell line, AGS cells. We examined cell death by MTT assay and caspase 3 and 9 assay with 18α-GA. To examine the inhibitory effects of 18α-GA, sub-G1 analysis was done the AGS cells after 24 hours with 18α-GA. Also, to investigate the inhibitory mechanisms of 18α-GA, mitogen-activated protein kinase pathways and reactive oxygen species (ROS) generation were examined. Results : 1. 18α-GA inhibited the growth of AGS cells in a dose-dependent fashion. 2. Sub-G1 fractions were significantly and dose-dependently increased by 18α-GA. 3. 18α-GA increased the caspase 3 and 9 activities in AGS cells. 4. 18α-GA inhibited proliferation of AGS cells via the modulation of c‑Jun N‑terminal kinase (JNK) signaling pathways, which results in the induction of apoptosis. 5. 18α-GA enhanced ROS accumulation in AGS cells. Conclusions : Our findings provide insight into unraveling the effects of 18α-GA in human gastric adenocarcinoma cells and developing therapeutic agents against gastric cancer.
Keywords
$18{\alpha}$-Glycyrrhetinic acid; Human gastric adenocarcinoma cell; AGS; Anti-cancer;
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1 Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10: 239-248.   DOI
2 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.   DOI
3 Orditura M, Galizia G, Sforza V, Gambardella V, Fabozzi A, Laterza MM, et al. Treatment of gastric cancer. World J Gastroenterol. 2014;20:1635-1649.   DOI
4 Sharma G, Kar S, Palit S, Das PK. 18beta-glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF-7 cells. J Cell Physiol. 2012;227:1923-1931.   DOI
5 Xiao Y, Xu J, Mao C, Jin M, Wu Q, Zou J, et al. 18Beta-glycyrrhetinic acid ameliorates acute Propionibacterium acnes-induced liver injury through inhibition of macrophage inflammatory protein-1alpha. J Biol Chem. 2010;285:1128-1137.   DOI
6 Jayasooriya RG, Dilshara MG, Park SR, Choi YH, Hyun JW, Chang WY, et al. $18{\beta}$ -Glycyrrhetinic acid suppresses TNF-${\alpha}$ induced matrix metalloproteinase-9 and vascular endothelial growth factor by suppressing the AKT-dependent NF-${\kappa}B$ pathway. Toxicol In Vitro. 2014;28:751-758.   DOI
7 Lin D, Zhong W, Li J, Zhang B. Song G, Hu T. Involvement of BID translocation in glycyrrhetinic acid and 11-deoxy glycyrrhetinic acid-induced attenuation of gastric cancer growth. Nutr Cancer. 2014;66:463-473.   DOI
8 Agarwal MK, Iqbal M, Athar M. Inhibitory effect of 18beta-glycyrrhetinic acid on 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor promotion in mice. Redox Rep. 2005;10:151-157.   DOI
9 Hoever G, Baltina L, Michaelis M, Kondratenko R, Baltina L, Tolstikov GA, et al. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J Med Chem. 2005; 48:1256-1259.   DOI
10 Takeuchi R, Hiratsuka K, Arikawa K, Ono M, Komiya M, Akimoto Y, et al. Possible pharmacotherapy for nifedipine-induced gingival overgrowth: 18alpha-glycyrrhetinic acid inhibits human gingival fibroblast growth. Br J Pharmacol. 2016;173:913-924.   DOI
11 Huang YC, Kuo CL, Lu KW, Lin JJ, Yang JL, Wu RS, et al. $18{\alpha}$-glycyrrhetinic acid induces apoptosis of HL-60 human leukemia cells through caspases- and mitochondriadependent signaling Pathways. Molecules. 2016;21:872.   DOI
12 Yin SY, Wei WC, Jian FY, Yang NS. Therapeutic applications of herbal medicines for cancer patients. Evid Based Complement Alternat Med. 2013;2013;302426.
13 Wang ZY, Nixon DW. Licorice and cancer. Nutr Cancer. 2001;39:1-11.   DOI
14 Nomura T, Fukai T. Phenolic constituents of licorice (Glycyrrhiza species). Fortschr Chem Org Naturst. 1998;73:1-158.
15 Baltina LA. Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine. Curr Med Chem. 2003;10:155-171.   DOI
16 Ikeda T, Yokomizo K, Okawa M, Tsuchihashi R, Kinjo J, Nohara T, et al. Anti-herpes virus type 1 activity of oleanane-type triterpenoids. Biol Pharm Bull. 2005;28: 1779-1781.   DOI
17 Rackova L, Jancinova V, Petrikova M, Drabikova K, Nosal R, Stefek M, et al. Mechanism of anti-inflammatory action of liquorice extract and glycyrrhizin. Nat Prod Res. 2007;21:1234-1241.   DOI
18 Thirugnanam S, Xu L, Ramaswamy K, Gnanasekar M. Glycyrrhizin induces apoptosis in prostate cancer cell lines DU-145 and LNCaP. Oncol Rep. 2008;20:1387-1392.
19 Niwa K, Lian Z, Onogi K, Yun W, Tang L, Mori H, et al. Preventive effects of glycyrrhizin on estrogen-related endometrial carcinogenesis in mice. Oncol Rep. 2007;17:617-622.
20 Zeng CX, Yang Q, Hu Q. A comparison of the distribution of two glycyrrhizic acid epimers in rat tissues. Eur J Drug Metab Pharmacokinet. 2006;31:253-258.   DOI
21 Ha YM, Cheung AP, Lim P. Chiral separation of glycyrrhetinic acid by high-performance liquid chromatography. J Pharm Biomed Anal. 1991;9:805-809.   DOI
22 Rossi T, Castelli M, Zandomeneghi G, Ruberto A, Benassi L, Magnoni C, et al. Selectivity of action of glycyrrhizin derivatives on the growth of MCF-7 and HEP-2 cells. Anticancer Res. 2003;23:3813-3818.
23 Shetty AV, Thirugnanam S, Dakshinamoorthy G, Samykutty A, Zheng G, Chen A, et al. $18{\alpha}$-glycyrrhetinic acid targets prostate cancer cells by down-regulating inflammation- related genes. Int J Oncol. 2011;39:635-640.   DOI
24 Debnath J, Baehrecke EH, Kroemer G. Does autophagy contribute to cell death?. Autophagy. 2005;1:66-74.   DOI
25 Cai H, Chen X, Zhang J, Wang J. $18{\beta}$-glycyrrhetinic acid inhibits migration and invasion of human gastric cancer cells via the ROS/PKC-${\alpha}$/ERK pathway. J Nat Med. 2018;72:252-259.   DOI
26 Cao D, Jia Z, You L, Wu Y, Hou Z, Suo Y, et al. $18{\beta}$-glycyrrhetinic acid suppresses gastric cancer by activation of miR-149-3p- Wnt-1 signaling. Oncotarget. 2016;7:71960-71973.   DOI
27 Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495-516.   DOI
28 Prevarskaya N, Skryma R, Shuba Y. Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?. Physiol Rev. 2018;98:559-621.   DOI
29 Kim BJ, Park EJ, Lee JH, Jeon JH, Kim SJ, So I. Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer. Cancer Sci. 2008;99:2502-2509.   DOI
30 Kim MC, Lee HJ, Lim B, Ha KT, Kim SY, So I, et al. Quercetin induces apoptosis by inhibiting MAPKs and TRPM7 channels in AGS cells. Int J Mol Med. 2014;33:1657-1663.   DOI
31 Almasi S, Sterea AM, Fernando W, Clements DR, Marcato P, Hoskin DW, et al. TRPM2 ion channel promotes gastric cancer migration, invasion and tumor growth through the AKT signaling pathway. Sci Rep. 2019;9:4182.   DOI
32 Luo Z, Zeng H, Ye Y, Liu L, Li S, Zhang J, et al. Safflower polysaccharide inhibits the proliferation and metastasis of MCF-7 breast cancer cell. Mol Med Rep. 2015;11:4611-4616.   DOI
33 Crociani O, Lastraioli E, Boni L, Pillozzi S, Romoli MR, D'Amico M, et al. hERG1 channels regulate VEGF-A secretion in human gastric cancer: clinicopathological correlations and therapeutical implications. Clin Cancer Res. 2014;20:1502-1512.   DOI