Ellagic acid inhibits gastric cancer cells by modulating oxidative stress and inducing apoptosis

Abstract

Objective: To evaluate the anticancer effect of ellagic acid on gastric cancer cells. Methods: MTT assay was used to evaluate the effect of ellagic acid at different concentrations (0.5-100 μg/mL) on gastric cancer AGS cells. RT-qPCR and Western blot analyses were applied to assess apoptosis (BCL-2, CASP-3, and BAX) and autophagy (LC3, ATG5, and BECN1) in AGS cells treated with ellagic acid. The expression of invasion-related markers including TP53, CDKN2A, and PTEN was determined. In addition, cell cycle markers including cyclin A, B, D, and E were measured by ELISA. Oxidative stress markers were evaluated using spectrophotometry. Results: Ellagic acid inhibited the proliferation of AGS cells in a concentration- and time-dependent manner. The expression of BCL-2 was significantly decreased (P<0.05) and CASP-3 and BAX were markedly increased (P<0.01) in AGS cells treated with ellagic acid. However, this compound induced no significant changes in the expression levels of LC3, ATG5, and BECN1 (P>0.05). Moreover, the oxidative stress markers including SOD, TAC, and MDA were increased by ellagic acid (P<0.01). Conclusions: Ellagic acid can inhibit cell proliferation, induce apoptosis, and modulate oxidative stress in AGS cells. However, further in vivo and molecular studies are needed to verify its anticancer efficacy.

Keywords

Ellagic acid / Gastric cancer / Apoptosis / Autophagy / Metastasis / Proliferation

Conflict of interest statement

The authors report no conflict of interest.

Funding

This study was supported by the Heilongjiang Provincial Natural Science Foundation of China (LH2022H063).

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

CL contributed to the conception of the study. CL and JZ performed the experiments and data interpretation, and JZ wrote the manuscript. All authors read and approved the manuscript for submission and publication.

References

[1] Chen J, Zhu Y, Wang Y. Emerging noninvasive neuromodulation methods for functional gastrointestinal diseases. J Transl Int Med 2023; 10(4): 281-285.

[2] Sun K, Lv H, Chen B, Nie C, Zhao J, Wang S, et al. Dawning precision treatment for gastric cancer: The latest biomarkers. J Transl Int Med 2021; 9(4): 228-230.

[3] Yin Y, Liang H, Wei N, Zheng Z. Prevalence of chronic atrophic gastritis worldwide from 2010 to 2020: An updated systematic review and meta-analysis. Ann Palliat Med 2022; 11: 3697-3703.

[4] Fang X, Xu J, Jin K, Qian J. Combining of immunotherapeutic approaches with chemotherapy for treatment of gastric cancer: Achievements and limitations. Int Immunopharmacol 2023; 118. doi: 10.1016/j.intimp.2023.110062.

[5] Samare-Najaf M, Zal F, Safari S, Koohpeyma F, Jamali N. Stereological and histopathological evaluation of doxorubicin-induced toxicity in female rats’ ovary and uterus and palliative effects of quercetin and vitamin E. Hum Exp Toxicol 2020; 39(12): 1710-1724.

[6] Samare-Najaf M, Samareh A, Jamali N, Abbasi A, Clark CC, Khorchani MJ, et al. Adverse effects and safety of Etirinotecan Pegol, a novel topoisomerase inhibitor, in cancer treatment: A systematic review. Curr Cancer Ther Rev 2021; 17(3): 234-243.

[7] Sanders B, Ray AM, Goldberg S, Clark T, McDaniel HR, Atlas SE, et al. Anti-cancer effects of aloe-emodin: A systematic review. J Clin Trans Res 2018; 3(3): 283.

[8] Kasi A, Allen J, Mehta K, Dandawate P, Saha S, Bossmann S, et al. Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy. J Clin Trans Res 2021; 7(2): 257-262.

[9] Pérez-Pedroza R, Al-Jalih F, Xu J, Moretti M, Briola GR, Hauser CA. Fabrication of lumen-forming colorectal cancer organoids using a newly designed lamininderived bioink. Int J Bioprint 2023; 9(1). doi: 10.18063/ijb.v9i1.633.

[10] Wang P, Sun L, Li C, Jin B, Yang H, Wu B, et al. Study on drug screening multicellular model for colorectal cancer constructed by three-dimensional bioprinting technology. Int J Bioprint 2023; 9(3). doi: 10.18063/ijb.694.

[11] Le TT, Nguyen PH, Nguyen TN. Ardisia gigantifolia ethanolic extract inhibits cell proliferation and targets cancer stem cells in gastric cancer. Asian Pac J Trop Biomed 2023; 13(6): 258-267.

[12] Rostami A, Vakili S, Koohpeyma F, Jahromi BN, Aghajari ZA, Mahmoudikohani F, et al. Ellagic acid effects on testis, sex hormones, oxidative stress, and apoptosis in the relative sterility rat model following busulfan administration. BMC Complement Med Ther 2022; 22(1): 1-14.

[13] Tasaki M, Umemura T, Maeda M, Ishii Y, Okamura T, Inoue T, et al. Safety assessment of ellagic acid, a food additive, in a subchronic toxicity study using F344 rats. Food Chem Toxicol 2008; 46(3): 1119-1124.

[14] Kaur H, Ghosh S, Kumar P, Basu B, Nagpal K. Ellagic acid-loaded, tween 80-coated, chitosan nanoparticles as a promising therapeutic approach against breast cancer: In-vitro and in-vivo study. Life Sci 2021; 284. doi: 10.1016/j.lfs.2021.119927.

[15] Liu Z, Huang H, Yu Y, Li L, Shi X, Wang F. Exploring the mechanism of ellagic acid against gastric cancer based on bioinformatics analysis and network pharmacology. J Cell Mol Med 2023; 27(23): 3878-3896.

[16] Barroso-Chinea P, Luis-Ravelo D, Fumagallo-Reading F, Castro-Hernandez J, Salas-Hernandez J, Rodriguez-Nuñez J, et al. DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis. Autophagy 2020; 16(7): 1279-1295.

[17] Samare-Najaf M, Zal F, Safari S. Primary and secondary markers of doxorubicin-induced female infertility and the alleviative properties of quercetin and vitamin E in a rat model. Reprod Toxicol 2020; 96: 316-326.

[18] Kisacam MA. Ellagic acid exerts apoptotic and antiangiogenic activity on human intestinal cancer (Caco-2) cell line. Int J Acad Med Pharm 2022; 4(2): 59-63.

[19] Gao Z, Jiang J, Hou L, Zhang B. Dysregulation of miR-144-5p/RNF187 axis contributes to the progression of colorectal cancer. J Transl Int Med 2022; 10(1): 65-75.

[20] Samare-Najaf M, Zal F, Jamali N, Vakili S, Khodabandeh Z. Do quercetin and vitamin E properties preclude doxorubicin-induced stress and inflammation in reproductive tissues? Curr Cancer Ther Rev 2022; 18(4): 292-302.

[21] Xue P, Zhang G, Zhang J, Ren L. Synergism of ellagic acid in combination with radiotherapy and chemotherapy for cancer treatment. Phytomedicine 2022; 99. doi: 10.1016/j.phymed.2022.153998.

[22] Zheng JH, Viacava Follis A, Kriwacki RW, Moldoveanu T. Discoveries and controversies in BCL-2 protein-mediated apoptosis. FEBS J 2016; 283(14): 2690-2700.

[23] Chandurkar P, Dhokne M, Wankhede N, Mangrulkar S, Taksande B, Upaganlawar A, et al. Modulation of mitochondrial function in elderly brain: Involvement of autophagy and apoptosis. INNOSC Theranostics Pharmacol Sci 2023; 4(2): 33-45.

[24] Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ 2015; 22(4): 526-539.

[25] Shariati A, Raberi VS, Masumi M, Tarbiat A, Rastgoo E, Faramarzzadeh R. The regulation of pyroptosis and ferroptosis by microRNAs in cardiovascular diseases: Pyroptosis and ferroptosis regulation by micro RNAs. Galen Med J 2023; 12: e2933-e.

[26] Edderkaoui M, Odinokova I, Ohno I, Gukovsky I, Go VLW, Pandol SJ, et al. Ellagic acid induces apoptosis through inhibition of nuclear factor κB in pancreatic cancer cells. World J Gastoentrol 2008; 14(23): 3672-3680.

[27] Lu G, Wang X, Cheng M, Wang S, Ma K. The multifaceted mechanisms of ellagic acid in the treatment of tumors: State-of-the-art. Biomed Pharmacother 2023; 165. doi: 10.1016/j.biopha.2023.115132.

[28] Samare-Najaf M, Neisy A, Samareh A, Moghadam D, Jamali N, Zarei R, et al. The constructive and destructive impact of autophagy on both genders’ reproducibility, a comprehensive review. Autophagy 2023; 19(12): 3033-3061.

[29] Tran S, Fairlie WD, Lee EF. BECLIN1: Protein structure, function and regulation. Cells 2021; 10(6): 1522.

[30] Cao W, Li J, Yang K, Cao D. An overview of autophagy: Mechanism, regulation and research progress. Bull Cancer 2021; 108(3): 304-322.

[31] Ni X, Shang FS, Wang TF, Wu DJ, Chen DG, Zhuang B. Ellagic acid induces apoptosis and autophagy in colon cancer through the AMPK/mTOR pathway. Tissue Cell 2023; 81. doi: 10.1016/j.tice.2023.102032.

[32] Chung YC, Lu LC, Tsai MH, Chen YJ, Chen YY, Yao SP, et al. The inhibitory effect of ellagic acid on cell growth of ovarian carcinoma cells. Evid Based Complement Alternat Med 2013; 2013. doi: 10.1155/2013/306705.

[33] Wang Y, Xiong H, Liu D, Hill C, Ertay A, Li J, et al. Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. Autophagy 2019; 15(5): 886-899.

[34] Rohatgi RA, Janusis J, Leonard D, Bellvé KD, Fogarty KE, Baehrecke EH, et al. Beclin 1 regulates growth factor receptor signaling in breast cancer. Oncogene 2015; 34(42): 5352-5362.

[35] Veiseh O, Kievit FM, Ellenbogen RG, Zhang M. Cancer cell invasion: Treatment and monitoring opportunities in nanomedicine. Adv Drug Deliv Rev 2011; 63(8): 582-596.

[36] Mantovani F, Collavin L, Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ 2019; 26(2): 199-212.

[37] Parambil ST, Antony GR, Littleflower AB, Subhadradevi L. Verteporfin induces YAP-dependent cell cycle arrest and caspase-mediated cellular apoptosis in triple-negative breast cancer cells. Gene Protein Dis 2023; 2(2). doi: 10.36922/gpd.0658.

[38] Lorenzo JM, Munekata PE, Putnik P, Kovačević DB, Muchenje V, Barba FJ. Sources, chemistry, and biological potential of ellagitannins and ellagic acid derivatives. In: Studies in natural products chemistry. Elsevier; 2019, p. 189-221.

[39] Javed A, Yarmohammadi M, Korkmaz KS, Rubio-Tomás T. The regulation of cyclins and cyclin-dependent kinases in the development of gastric cancer. Int J Mol Sci 2023; 24(3). doi: 10.3390/ijms24032848.

[40] Rezaeian A-H, Inuzuka H, Wei W. Insights into the aberrant CDK4/6 signaling pathway as a therapeutic target in tumorigenesis. Adv Protein Chem Struct Biol 2023; 135: 179-201.

[41] Golmohammadi M, Zamanian MY, Jalal SM, Noraldeen SAM, Ramírez-Coronel AA, Oudaha KH, et al. A comprehensive review on ellagic acid in breast cancer treatment: From cellular effects to molecular mechanisms of action. Food Sci Nutr 2023; 11(12): 7458-7468.

[42] Vijayalakshmi A, Anitha V, Al-Antary TMM. Inhibitory effect of Solanum xanthocarpum on the growth of KB human oral cancer cell line in vitro through ROS-induced mitochondrial pathway. Glob Transl Med 2022; 1(1): 1-8.

[43] Chen Y, McMillan-Ward E, Kong J, Israels S, Gibson S. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 2008; 15(1): 171-182.

[44] Sun L, Dong H, Zhang W, Wang N, Ni N, Bai X, et al. Lipid peroxidation, GSH depletion, and SLC7A11 inhibition are common causes of EMT and ferroptosis in A549 cells, but different in specific mechanisms. DNA Cell Biol 2021; 40(2): 172-183.