AccScience Publishing / CP / Volume 7 / Issue 1 /
Submit to CP
Cite this article
5
Download
77
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Evaluating anticancer effects of geraniin supplementation in a syngeneic mouse model of breast cancer: Identification of differentially regulated plasma proteins

Heng Jia Hui1 ,  Catherine Ng Zhi Xin2 ,  Nur Diana Anuar3 ,  Jeya Seela Anandha Rao4 ,  Nurul H Rutt3 ,  Nurul Shielawati Mohamed Rosli3 ,  Sunil Pazhayanur Venkateswaran4* ,  Ammu Kutty Radhakrishnan5
Show Less
1 Department of Pediatrics, Sydney Children’s Hospital, Randwick, New South Wales, Australia
2 Department of Emergency, Blacktown Hospital, Sydney, New South Wales, Australia
3 Sengenics Corporation, Kuala Lumpur, Malaysia
4 Department of Pathology and Pharmacology, School of Medicine, IMU University, Kuala Lumpur, Malaysia
5 Food as Medicine Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor, Malaysia
CP 2025, 7(1), 83–95;
Submitted: 19 December 2024 | Revised: 26 February 2025 | Accepted: 20 March 2025 | Published: 15 April 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Geraniin, an ellagitannin present in many seeds, nuts, fruits, and plants, has anticancer, antioxidant, antiviral, antimicrobial, antimutagenic, cardiovascular protective, and hypoglycemic properties. Geraniin was tested for its anticancer and plasma protein-modifying properties in a syngeneic mouse model of breast cancer (BC). A mouse mammary cancer cell line (4T1) was injected into the mammary pad of female BALB/c mice to produce BC. Daily oral gavage of geraniin (0.5 mg) or soy oil was given to animals having visible tumors. For 6 – 7 weeks, tumor growth was evaluated. At postmortem, cancer tissue was removed for histopathology, and the plasma was analyzed using a commercial protein array platform. Geraniin supplementation reduced tumor growth and liver metastasis (p<0.05) and altered 20 plasma proteins, including Tropomyosin 3 (TPM3), catenin beta-1 (CTNNB1), hemopoietic lineage cell-specific protein 1 (HCLS1), and Serine/threonine-protein kinase 10 (STK10). Six biomarkers (RAD23 homolog B, HCLS1, CTNNB1, A type of type ll restriction enzyme, TPM3, and STK10) were higher in geraniin-treated samples than in control samples, regardless of tumor induction. Monitoring plasma protein expression in a BC model indicated tumor progression, metastasis, and potential diagnostic or therapeutic biomarkers. The 4T1 cell line, an exceptionally invasive mammary cancer model, accurately replicates human triple-negative BC, making it valuable for investigating metastatic behavior and treatment. Plasma protein dynamics in this model may identify tumor aggressiveness regulators and therapeutic targets. Geraniin possesses antitumor and anti-metastasis characteristics and could be developed to treat BC. The autoantibody response toward these antigens and fluctuation in the response could suggest a potential marker or a predictive marker toward treatment with geraniin.

Keywords
Geraniin
Breast cancer
Mouse model
Protein array
Biomarker
Funding
This study was supported by two research grants from IMU University (BMS I/2018[01] and BMS I/2018[14]) that supported the research activities of two 3rd-year undergraduate medical students.
Conflict of interest
Nur Diana Anuar, Nurul H Rutt, and Nurul Shielawati Mohamed Rosli are employees of the Sengenics Corporation company. This has not influenced the content of the manuscript.) No reference to the author’s company is made, but it is declared for full transparency.
References
  1. DeSantis CE, Bray F, Ferlay J, Lortet-Tieulent J, Anderson BO, Jemal A. International variation in female breast cancer incidence and mortality rates. Cancer Epidemiol Biomarkers Prev. 2015;24(10):1495-1506. doi: 10.1158/1055-9965.EPI-15-0535

 

  1. Wild CP, Weiderpass E, Stewart BW, editors. World Cancer Report: Cancer Research for Cancer Prevention. Lyon, FR: International Agency for Research on Cancer; 2020. Available from: https://publications.iarc.fr/586 [Last accessed on 2025 Apr 14].

 

  1. U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2022. Available from: https:// www.cdc.gov/cancer/dataviz [Last accessed on 2025 Apr 14].

 

  1. Haron @Harun MAB, Yusof SNB. Summary of Malaysia National Cancer Registry Report 2017-2021. Cancer Registry Report, Institut Kanser Negara, Ministry of Health; 2021. Available from: https://nci.moh.gov.my/images/pdf_ folder/summary-of-malaysia-national-cancer-registry-report-2017-2021.pdf [Last accessed on 2025 Feb 23].

 

  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660

 

  1. Arbyn M, Weiderpass E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018: A worldwide analysis [published correction appears in Lancet Glob Health. 2022;10(1):e41. doi: 10.1016/S2214-109X(21)00554-4]. Lancet Glob Health. 2020;8(2):e191-e203. doi: 10.1016/S2214-109X(19)30482-6

 

  1. Abotaleb M, Kubatka P, Caprnda M, et al. Chemotherapeutic agents for the treatment of metastatic breast cancer: An update. Biomed Pharmacother. 2018;101:458-477. doi: 10.1016/j.biopha.2018.02.108

 

  1. Jordan VC. Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discov. 2003;2(3):205-213. doi: 10.1038/nrd1031

 

  1. Patani N, Mokbel K. Herceptin and breast cancer: An overview for surgeons. Surg Oncol. 2010;19(1):e11-e21. doi: 10.1016/j.suronc.2008.11.001

 

  1. Gezgin S, Dinh T. The simultaneous delivery of paclitaxel and Herceptin® using solid lipid nanoparticles: In vitro evaluation. J Drug Deliv Sci Technol. 2016;35:98-105. doi: 10.1016/j.jddst.2016.06.010

 

  1. Elserafi MM, Zeeneldin AA, Abdelsalam IM, Nassar HR, Moneer MM, Buhoush WH. First-line paclitaxel and cisplatin used sequentially or in combination in metastatic breast cancer: A phase II randomized study. J Egypt Natl Canc Inst. 2018;30(1):13-20. doi: 10.1016/j.jnci.2018.01.002

 

  1. Morrow M, Jordan VC. Risk factors and the prevention of breast cancer with tamoxifen. Cancer Surv. 1993;18:211-229.

 

  1. Tang Y, Wang Y, Kiani MF, Wang B. Classification, treatment strategy, and associated drug resistance in breast cancer. Clin Breast Cancer. 2016;16(5):335-343. doi: 10.1016/j.clbc.2016.05.012

 

  1. Jordan VC. Tamoxifen: Toxicities and drug resistance during the treatment and prevention of breast cancer. Annu Rev Pharmacol Toxicol. 1995;35(1):195-211. doi: 10.1146/annurev.pa.35.040195.001211

 

  1. Brems C, Barnett J, Parret VC, Metzger J, Johnson ME. Alternative and complementary treatment needs and experiences of women with breast cancer. J Altern Complement Med. 2013;19(7):657-663. doi: 10.1089/acm.2012.0161

 

  1. Radice D, Redaelli A. Breast cancer management: Quality-of-life and cost considerations. Pharmacoeconomics. 2003;21(6):383-396. doi: 10.2165/00019053-200321060-00003

 

  1. Okuda T, Yoshida T, Nayeshiro H. Geraniin, a new ellagitannin from Geranium thunbergii. Tetrahedron Lett. 1976;17(41):3721-3722. doi: 10.1016/s0040-4039(00)93091-0

 

  1. Koponen JM, Happonen AM, Mattila PH, Törrönen AR. Contents of anthocyanins and ellagitannins in selected foods consumed in Finland. J Agric Food Chem. 2007;55(4):1612-1619. doi: 10.1021/jf062897a

 

  1. Lee JH, Talcott ST. Ellagic acid and ellagitannins affect on sedimentation in muscadine juice and wine. J Agric Food Chem. 2002;50(14):3971-3976. doi: 10.1021/jf011587j

 

  1. Gonçalves B, Borges O, Costa HS, Bennett R, Santos M, Silva AP. Metabolite composition of chestnut (Castanea sativa Mill.) upon cooking: Proximate analysis, fibre, organic acids and phenolics. Food Chem. 2010;122(1):154-160. doi: 10.1016/j.foodchem.2010.02.032

 

  1. Villarreal-Lozoya JE, Lombardini L, Cisneros-Zevallos L. Phytochemical constituents and antioxidant capacity of different pecan [Carya illinoinensis (Wangenh.) K. Koch] cultivars. Food Chem. 2007;102(4):1241-1249. doi: 10.1016/j.foodchem.2006.07.024

 

  1. Perera A, Ton SH, Palanisamy UD. Perspectives on geraniin, a multifunctional natural bioactive compound. Trends Food Sci Technol. 2015;44(2):243-257. doi: 10.1016/j.tifs.2015.04.010

 

  1. Cheng HS, Ton SH, Abdul Kadir K. Ellagitannin geraniin: A review of the natural sources, biosynthesis, pharmacokinetics and biological effects. Phytochem Rev. 2017;16(1):159-193. doi: 10.1007/s11101-016-9464-2

 

  1. Chung APYS, Gurtu S, Chakravarthi S, Moorthy M, Palanisamy UD. Geraniin protects high-fat diet-induced oxidative stress in sprague dawley rats. Front Nutr. 2018;5:17. doi: 10.3389/fnut.2018.00017

 

  1. Bing SJ, Ha D, Kim MJ, et al. Geraniin down regulates gamma radiation-induced apoptosis by suppressing DNA damage. Food Chem Toxicol. 2013;57:147-153. doi: 10.1016/j.fct.2013.03.022

 

  1. Yang Y, Zhang L, Fan X, Qin C, Liu J. Antiviral effect of geraniin on human enterovirus 71 in vitro and in vivo. Bioorg Med Chem Lett. 2012;22(6):2209-2211. doi: 10.1016/j.bmcl.2012.01.102

 

  1. Bigos M, Wasiela M, Kalemba D, Sienkiewicz M. Antimicrobial activity of geranium oil against clinical strains of Staphylococcus aureus. Molecules. 2012;17(9):10276- 10291. doi: 10.3390/molecules170910276

 

  1. Wang P, Qiao Q, Li J, Wang W, Yao LP, Fu YJ. Inhibitory effects of geraniin on LPS-induced inflammation via regulating NF-κB and Nrf2 pathways in RAW 264.7 cells. Chem Biol Interact. 2016;253:134-142. doi: 10.1016/j.cbi.2016.05.014

 

  1. Shim JU, Oh PS, Lim KT. Anti-inflammatory activity of ethanol extract from Geranium sibiricum linne. J Ethnopharmacol. 2009;126(1):90-95. doi: 10.1016/j.jep.2009.08.004

 

  1. Ren Z, Zou W, Cui J, Liu L, Qing Y, Li Y. Geraniin suppresses tumor cell growth and triggers apoptosis in human glioma via inhibition of STAT3 signaling. Cytotechnology. 2017;69(5):765-773. doi: 10.1007/s10616-017-0085-4

 

  1. Zhai JW, Gao C, Ma WD, et al. Geraniin induces apoptosis of human breast cancer cells MCF-7 via ROS-mediated stimulation of p38 MAPK. Toxicol Mech Methods. 2016;26(5):311-318. doi: 10.3109/15376516.2016.1139025

 

  1. Guo X, Dai X, Ni J, Ma X, Xue J, Wang X. Geraniin differentially modulates chromosome stability of colon cancer and noncancerous cells by oppositely regulating their spindle assembly checkpoint. Environ Mol Mutagen. 2019;60(3):254-268. doi: 10.1002/em.22265

 

  1. Zhou LA, Liu TB, Lü HN. Geraniin inhibits proliferation and induces apoptosis through inhibition of phosphatidylinositol 3-kinase/Akt pathway in human colorectal cancer in vitro and in vivo. Anticancer Drugs. 2020;31(6):575-582. doi: 10.1097/CAD.0000000000000929

 

  1. Wang X, Chen Z, Li X, Jiang ZK, Zhao YQ, Ping FF. Geraniin suppresses ovarian cancer growth through inhibition of NF-κB activation and downregulation of Mcl-1 expression. J Biochem Mol Toxicol. 2017;31(9): e21929. doi: 10.1002/jbt.21929

 

  1. Li J, Wang S, Yin J, Pan L. Geraniin induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro and in vivo. Can J Physiol Pharmacol. 2013;91(12):1016- 1024. doi: 10.1139/cjpp-2013-0140

 

  1. Wang Y, Wan D, Zhou R, Zhong W, Lu S, Chai Y. Geraniin inhibits migration and invasion of human osteosarcoma cancer cells through regulation of PI3K/Akt and ERK1/2 signaling pathways. Anticancer Drugs. 2017;28(9):959-966. doi: 10.1097/CAD.0000000000000535

 

  1. Abdul Hafid SR, Chakravarthi S, Nesaretnam K, Radhakrishnan AK. Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: A murine model of breast cancer. PLoS One. 2013;8(9):e74753. doi: 10.1371/journal.pone.0074753

 

  1. Selvaduray KR, Radhakrishnan AK, Kutty MK, Nesaretnam K. Palm tocotrienols inhibit proliferation of murine mammary cancer cells and induce expression of interleukin-24 mRNA. J Interferon Cytokine Res. 2010;30(12):909-916. doi: 10.1089/jir.2010.0021

 

  1. Silva VL, Ferreira D, Nobrega FL, Martins IM, Kluskens LD, Rodrigues LR. Selection of novel peptides homing the 4T1 CELL line: Exploring alternative targets for triple negative breast cancer. PLoS One. 2016;11(8):e0161290. doi: 10.1371/journal.pone.0161290

 

  1. Singh M, Ramos I, Asafu-Adjei D, et al. Curcumin improves the therapeutic efficacy of Listeria(at)-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1. Cancer Med. 2013;2(4):571-582. doi: 10.1002/cam4.94

 

  1. Tao K, Fang M, Alroy J, Sahagian GG. Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer. 2008;8:228. doi: 10.1186/1471-2407-8-228

 

  1. Sumera A, Anuar ND, Radhakrishnan AK, et al. A novel method to identify autoantibodies against putative target proteins in serum from beta-thalassemia major: A pilot study. Biomedicines. 2020;8(5):97. doi: 10.3390/biomedicines8050097

 

  1. Ko H. Geraniin inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration, invasion and anoikis resistance. Bioorg Med Chem Lett. 2015;25(17):3529-3534. doi: 10.1016/j.bmcl.2015.06.093

 

  1. Yang CM, Ji S, Li Y, Fu LY, Jiang T, Meng FD. β-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma. Onco Targets Ther. 2017;10:711-724. doi: 10.2147/OTT.S117933

 

  1. Gao C, Wang Y, Broaddus R, Sun L, Xue F, Zhang W. Exon 3 mutations of CTNNB1 drive tumorigenesis: A review. Oncotarget. 2018;9(4):5492-5508. doi: 10.18632/oncotarget.23695

 

  1. Shan S, Lv Q, Zhao Y, et al. Wnt/β-catenin pathway is required for epithelial to mesenchymal transition in CXCL12 over expressed breast cancer cells. Int J Clin Exp Pathol. 2015;8(10):12357-12367.

 

  1. Xu J, Prosperi JR, Choudhury N, Olopade OI, Goss KH. β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells. PLoS One. 2015;10(2):e0117097. doi: 10.1371/journal.pone.0117097

 

  1. van Schie EH, van Amerongen R. Aberrant WNT/CTNNB1 signaling as a therapeutic target in human breast cancer: Weighing the evidence. Front Cell Dev Biol. 2020;8:25. doi: 10.3389/fcell.2020.00025

 

  1. Wade SL, Auble DT. The Rad23 ubiquitin receptor, the proteasome and functional specificity in transcriptional control. Transcription. 2010;1(1):22-26. doi: 10.4161/trns.1.1.12201

 

  1. Linge A, Maurya P, Friedrich K, et al. Identification and functional validation of RAD23B as a potential protein in human breast cancer progression. J Proteome Res. 2014;13(7):3212-3222. doi: 10.1021/pr4012156

 

  1. Chen L, Madura K. Evidence for distinct functions for human DNA repair factors hHR23A and hHR23B. FEBS Lett. 2006;580(14):3401-3408. doi: 10.1016/j.febslet.2006.05.012

 

  1. Friedberg EC. How nucleotide excision repair protects against cancer. Nat Rev Cancer. 2001;1(1):22-33. doi: 10.1038/35094000

 

  1. Koya Y, Liu W, Yamakita Y, et al. Hematopoietic lineage cell-specific protein 1 (HS1), a hidden player in migration, invasion, and tumor formation, is over-expressed in ovarian carcinoma cells. Oncotarget. 2018;9(66):32609-32623. doi: 10.18632/oncotarget.25975

 

  1. Fischer U, Michel A, Meese EU. Expression of the gene for hematopoietic cell specific protein is not restricted to cells of hematopoietic origin. Int J Mol Med. 2005;15(4):611-615. doi: 10.3892/ijmm.15.4.611

 

  1. Janco M, Rynkiewicz MJ, Li L, et al. Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1. Sci Rep. 2019;9(1):11262. doi: 10.1038/s41598-019-47592-9

 

  1. Coombes JD, Schevzov G, Kan CY, et al. Ras transformation overrides a proliferation defect induced by Tpm3.1 knockout. Cell Mol Biol Lett. 2015;20(4):626-646. doi: 10.1515/cmble-2015-0037

 

  1. Dube S, Yalamanchili S, Lachant J, et al. Expression of tropomyosin 1 gene isoforms in human breast cancer cell lines. Int J Breast Cancer. 2015;2015:859427. doi: 10.1155/2015/859427

 

  1. Thitilertdecha N, Chaiwut P, Saewan N. In vitro antioxidant potential of Nephelium lappaceum L. rind extracts and geraniin on human epidermal keratinocytes. Biocatal Agric Biotechnol. 2020;23(101482):101482. doi: 10.1016/j.bcab.2019.101482

 

  1. Prabakaran NN, Prasad S, Krishnan K, Venkatabalasubramanian S. Geraniin: A dietary ellagitannin as a modulator of signalling pathways in cancer progression. Fitoterapia. 2024;177(106107):106107. doi: 10.1016/j.fitote.2024.106107

 

  1. Palanisamy DT, Perumal K. The Effects of Geraniin on Human Breast Cancer Cell (MCF-7 and MDA-MB-231) Metabolism. (Doctoral dissertation). International Medical University; 2018.

 

Next article in this issue
Share
Back to top
Cancer Plus, Electronic ISSN: 2661-3840 Print ISSN: 2661-3832, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept