Seselin promotes cisplatin-induced apoptosis of AGS gastric cancer cells by inhibiting β-catenin expression




seselin, cisplatin, coumarin, apoptosis, complementary therapy


Paper description:

  • Seselin, one of coumarin derivatives, has an anticancer effect but its detailed mechanism of action is unknown.
  • Human gastric adenocarcinoma cells (AGS) were treated with cisplatin to investigate the effect of seselin on cell death. The role of seselin and cisplatin in cells was determined using a phospho-kinase array.
  • Seselin can regulate the level of β-catenin by modulating the phosphorylation of glycogen synthase kinase-3 beta (GSK-3β), extracellular-signal-regulated kinase (ERK) and Src tyrosine kinase, and can cooperate with cisplatin to promote cancer cell apoptosis.
  • Seselin can be used as an adjuvant drug in chemotherapy to reduce the clinical dosage of chemotherapy.

Abstract: Gastric cancer is a commonly diagnosed form of cancer, and cisplatin is commonly used as a chemotherapy drug for treating it. However, the side effects of cisplatin may reduce patients’ willingness to use it. Seselin, a derivative of coumarin, has been found to have anticancer properties as well as anticoagulant effects. In this study, we investigated the effect of seselin on promoting cisplatin-induced gastric cancer cell death using the cell proliferation reagent WST-1, BrdU incorporation and lactate dehydrogenase release. The role of seselin and cisplatin in the apoptosis of gastric cancer cells was analyzed using a phospho-kinase array and Western blot analysis. Seselin did not affect G2/M stasis, but it promoted cell death in AGS cells treated with cisplatin. Phospho-kinase array analysis revealed that cisplatin regulates intracellular p53 phosphorylation, while seselin regulates intracellular β-catenin expression by affecting the phosphorylation of glycogen synthase kinase-3 beta (GSK-3β), extracellular-signal-regulated kinase (ERK) and Src tyrosine kinase. Seselin and cisplatin promote the apoptosis of gastric cancer cells by the synergistic effect of two distinct signaling pathways. These findings suggest that seselin may be used as a complementary therapy to reduce the clinical dose of chemotherapy.


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Morgan E, Arnold M, Camargo MC, Gini A, Kunzmann AT, Matsuda T, Meheus F, Verhoeven RHA, Vignat J, Laversanne M, Ferlay, J, Soerjomataram, I. The current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: A population-based modelling study. EClinicalMedicine. 2022;47:101404.

Li Y, Feng A, Zheng S, Chen C, Lyu J. Recent Estimates and Predictions of 5-Year Survival in Patients with Gastric Cancer: A Model-Based Period Analysis. Cancer Control. 2022:29:10732748221099227.

Petrelli F, Zaniboni A, Coinu A, Cabiddu M, Ghilardi M, Sgroi G, Barni S. Cisplatin or not in advanced gastric cancer: a systematic review and meta-analysis. PLoS One. 2013;8(12):e83022.

Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol. 2003;23(5):460-4.

Tang C, Livingston MJ, Safirstein R, Dong Z. Cisplatin nephrotoxicity: new insights and therapeutic implications. Nat Rev Nephrol. 2023;19(1):53-72.

Tang Q, Wang X, Jin H, Mi Y, Liu L, Dong M, Chen Y, Zou Z. Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies. Eur J Pharm Biopharm. 2021;163:60-71.

Zhang X, Qiu H, Li C, Cai P, Qi F. The positive role of traditional Chinese medicine as an adjunctive therapy for cancer. Biosci Trends. 2021;15(5):283-98.

Jiao L, Dong C, Liu J, Chen Z, Zhang L, Xu J, Shen X, Che J, Yang Y, Huang H Li, H, Sun J, Jiang Y, Mao Z, Chen P, Gong Y, Jin X, Xu L.Effects of Chinese Medicine as Adjunct Medication for Adjuvant Chemotherapy Treatments of Non-Small Cell Lung Cancer Patients. Sci Rep. 2017;7:46524.

Ling Y. Traditional Chinese medicine in the treatment of symptoms in patients with advanced cancer. Ann Palliat Med. 2013;2(3):141-52.

Xiang Y, Guo Z, Zhu P, Chen J, Huang Y. Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science. Cancer Med. 2019;8(5):1958-75.

Kasperkiewicz K, Ponczek MB, Owczarek J, Guga P, Budzisz E. Antagonists of Vitamin K-Popular Coumarin Drugs and New Synthetic and Natural Coumarin Derivatives. Molecules. 2020;25(6):1465.

Banikazemi Z, Mirazimi SM, Dashti F, Mazandaranian MR, Akbari M, Morshedi K, Aslanbeigi F, Rashidian A, Chamanara M, Hamblin MR, Taghizadeh M, Mirzaei H. Coumarins and Gastrointestinal Cancer: A New Therapeutic Option? Front Oncol. 2021;11:752784.

Nishino H, Okuyama T, Takata M, Shibata S, Tokuda H, Takayasu J, Hasegawa T, Nishino A, Ueyama H, Iwashima A. Studies on the anti-tumor-promoting activity of naturally occurring substances. IV. Pd-II [(+)anomalin, (+)praeruptorin B], a seselin-type coumarin, inhibits the promotion of skin tumor formation by 12-O-tetradecanoylphorbol-13-acetate in 7,12-dimethylbenz[a]anthracene-initiated mice. Carcinogenesis. 1990;11(9):1557-61.

Feng L, Sun Y, Song P, Xu L, Wu X, Wu X, Shen Y, Sun Y, Kong L, Wu X, Xu Q. Seselin ameliorates inflammation via targeting Jak2 to suppress the proinflammatory phenotype of macrophages. Br J Pharmacol. 2019;176(2):317-33.

Lu PH, Liao TH, Chen YH, Hsu YL, Kuo CY, Chan CC, Wang LK, Chern CY, Tsai FM. Coumarin Derivatives Inhibit ADP-Induced Platelet Activation and Aggregation. Molecules. 2022;27(13): 4054.

Liu CJ, Wang LK, Kuo CY, Chen ML, Tzeng IS, Tsai FM. Tournefortia sarmentosa Inhibits the Hydrogen Peroxide-Induced Death of H9c2 Cardiomyocytes. Evid Based Complement Alternat Med. 2021;2021:8219141.

Wang CH, Lu TJ, Wang LK, Wu CC, Chen ML, Kuo CY, Shyu RY, Tsai FM. Tazarotene-induced gene 1 interacts with Polo-like kinase 2 and inhibits cell proliferation in HCT116 colorectal cancer cells. Cell Biol Int. 2021;45(11):2347-56.

Trejo-Solis C, Escamilla-Ramirez A, Jimenez-Farfan D, Castillo-Rodriguez RA, Flores-Najera A, Cruz-Salgado A. Crosstalk of the Wnt/beta-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells. Pharmaceuticals (Basel). 2021;14(9):871.

Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ. 2015;22(4):526-39.

Li YJ, Wei ZM, Meng YX, Ji XR. Beta-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: relationships with carcinogenesis and metastasis. World J Gastroenterol. 2005;11(14):2117-23.

Nusse R, Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 2017;169(6):985-99.

Pelaz SG, Tabernero A. Src: coordinating metabolism in cancer. Oncogene. 2022;41(45):4917-28.

Zhang Y, Wang X. Targeting the Wnt/beta-catenin signaling pathway in cancer. J Hematol Oncol. 2020;13(1):165.

He R, Du S, Lei T, Xie X, Wang Y. Glycogen synthase kinase 3beta in tumorigenesis and oncotherapy (Review). Oncol Rep. 2020;44(6):2373-85.

Chiurillo MA. Role of the Wnt/beta-catenin pathway in gastric cancer: An in-depth literature review. World J Exp Med. 2015;5(2):84-102.

Mello AA, Leal MF, Rey JA, Pinto GR, Lamarao LM, Montenegro RC, Alves AP, Assumpcao PP, Borges Bdo N, Smith MC, Burbano, RR. Deregulated Expression of SRC, LYN and CKB Kinases by DNA Methylation and Its Potential Role in Gastric Cancer Invasiveness and Metastasis. PLoS One. 2015;10(10):e0140492.

DE Fátima Ferreira Borges DA Costa J, DE Castro Sant' Anna C, Muniz JAPC, DA Rocha CAM, Lamarão LM, DE Fátima Aquino Moreira Nunes C, DE Assumpção PP, Burbano RR.. Deregulation of the SRC Family Tyrosine Kinases in Gastric Carcinogenesis in Non-human Primates. Anticancer Res. 2018;38(11):6317-20.

Lee SK, Hwang JH, Choi KY. Interaction of the Wnt/beta-catenin and RAS-ERK pathways involving co-stabilization of both beta-catenin and RAS plays important roles in the colorectal tumorigenesis. Adv Biol Regul. 2018;68:46-54.

Ryu WJ, Han G, Lee SH, Choi KY. Suppression of Wnt/beta-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer. Biochem Biophys Res Commun. 2021;549:40-6.

Glibo M, Serman A, Karin-Kujundzic V, Bekavac Vlatkovic I, Miskovic B, Vranic S, Serman L. The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review. Bosn J Basic Med Sci. 2021;21(1):5-18.

Liebl MC, Hofmann TG. Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road. Bioessays. 2019;41(12):e1900127.

Yogosawa S, Yoshida K. Tumor suppressive role for kinases phosphorylating p53 in DNA damage-induced apoptosis. Cancer Sci. 2018;109(11):3376-82.

Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G, Yin G. Wnt/beta-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7(1):3.

Ali S, Tahir M, Khan AA, Chen XC, Ling M, Huang Y. Cisplatin Synergistically Enhances Antitumor Potency of Conditionally Replicating Adenovirus via p53 Dependent or Independent Pathways in Human Lung Carcinoma. Int J Mol Sci. 2019;20(5):1125.

Kleih M, Bopple K, Dong M, Gaissler A, Heine S, Olayioye MA, Aulitzky WE, Essmann F. Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells. Cell Death Dis. 2019;10(11):851.

Zamble DB, Jacks T, Lippard SJ. p53-Dependent and -independent responses to cisplatin in mouse testicular teratocarcinoma cells. Proc Natl Acad Sci U S A. 1998;95(11):6163-68.

McSweeney KR, Gadanec LK, Qaradakhi T, Ali BA, Zulli A, Apostolopoulos V. Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations. Cancers (Basel). 2021;13(7):1572.

Waissbluth S, Maass JC, Sanchez HA, Martinez AD. Supporting Cells and Their Potential Roles in Cisplatin-Induced Ototoxicity. Front Neurosci. 2022;16:867034.

Qin M, Huang Q, Yang X, Yu L, Tang Y, Zhang C, Qin D, Zou W, Deng J, Liu J, Hu H, Wang L, Wu, A, Wu J. Taxillus chinensis (DC.) Danser: a comprehensive review on botany, traditional uses, phytochemistry, pharmacology, and toxicology. Chin Med. 2022;17(1):136.

Meyer-Hamme G, Beckmann K, Radtke J, Efferth T, Greten HJ, Rostock M, Schroder S. A survey of chinese medicinal herbal treatment for chemotherapy-induced oral mucositis. Evid Based Complement Alternat Med. 2013;2013:284959.

Lai YJ, Tai CJ, Wang CW, Choong CY, Lee BH, Shi YC, Tai CJ. Anti-Cancer Activity of Solanum nigrum (AESN) through Suppression of Mitochondrial Function and Epithelial-Mesenchymal Transition (EMT) in Breast Cancer Cells. Molecules. 2016;21(5):553.

Nawaz A, Jamal A, Arif A, Parveen Z. In vitro cytotoxic potential of Solanum nigrum against human cancer cell lines. Saudi J Biol Sci. 2021;28(8):4786-92.

Ju SM, Kang JG, Bae JS, Pae HO, Lyu YS, Jeon BH. The Flavonoid Apigenin Ameliorates Cisplatin-Induced Nephrotoxicity through Reduction of p53 Activation and Promotion of PI3K/Akt Pathway in Human Renal Proximal Tubular Epithelial Cells. Evid Based Complement Alternat Med. 2015;2015:186436.

Wang SW, Xu Y, Weng YY, Fan XY, Bai YF, Zheng XY, Lou LJ, Zhang F. Astilbin ameliorates cisplatin-induced nephrotoxicity through reducing oxidative stress and inflammation. Food Chem Toxicol. 2018;114:227-36.

Kachadourian R, Leitner HM, Day BJ. Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: a role for glutathione depletion. Int J Oncol. 2007;31(1):161-8.

Mon MT, Yodkeeree S, Punfa W, Pompimon W, Limtrakul P. Alkaloids from Stephania venosa as Chemo-Sensitizers in SKOV3 Ovarian Cancer Cells via Akt/NF-kappaB Signaling. Chem Pharm Bull (Tokyo). 2018;66(2):162-9.

Zhang Y, Chen S, Wei C, Rankin GO, Rojanasakul Y, Ren N, Ye X, Chen YC. Dietary Compound Proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves inhibit angiogenesis and regulate cell cycle of cisplatin-resistant ovarian cancer cells via targeting Akt pathway. J Funct Foods. 2018;40:573-81.

Dasari S, Njiki S, Mbemi A, Yedjou CG, Tchounwou PB. Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy. Int J Mol Sci. 2022;23(3):1532.

Kim HJ, Choi JW, Ree J, Lim JS, Lee J, Kim JI, Thapa SB, Sohng JK, Park YI. Aloe emodin 3-O-glucoside inhibits cell growth and migration and induces apoptosis of non-small-cell lung cancer cells via suppressing MEK/ERK and Akt signalling pathways. Life Sci. 2022;300:120495.

Mijatovic S, Maksimovic-Ivanic D, Radovic J, Miljkovic D, Kaludjerovic GN, Sabo TJ, Trajkovic V. Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin. Cell Mol Life Sci. 2005;62(11):1275-82.

Chen SH, Chang JY. New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment. Int J Mol Sci. 2019;20(17):4136.

Li L, Liu HC, Wang C, Liu X, Hu FC, Xie N, Lu L, Chen X, Huang HZ. Overexpression of beta-Catenin Induces Cisplatin Resistance in Oral Squamous Cell Carcinoma. Biomed Res Int. 2016;2016:5378567.

Zhang J, Liu J, Li H, Wang J. beta-Catenin signaling pathway regulates cisplatin resistance in lung adenocarcinoma cells by upregulating Bcl-xl. Mol Med Rep. 2016;13(3):2543-51.




How to Cite

Shyu R-Y, Wang C-H, Wu C-C, Wang L-K, Tsai F-M. Seselin promotes cisplatin-induced apoptosis of AGS gastric cancer cells by inhibiting β-catenin expression. Arch Biol Sci [Internet]. 2023Oct.26 [cited 2024Feb.29];75(3):287-9. Available from: