Methanolic Leave Extract of Abrus precatorius Induces Natural Killer Cell Cytotoxicity Towards Breast Cancer Cells
DOI:
https://doi.org/10.54987/jobimb.v13i2.1129Keywords:
Abrus precatorius, Natural Killer cells, Breast cancer, MDA-MB-231, CytokinesAbstract
Abrus precatorius (A. precatorius) or locally known as rosary pea, is a type of bean that is traditionally used to treat respiratory disorders. Although the seeds are mainly used, there is lack of focus on the other plant parts, which may be important. In this study, the ability of the A. precatorius methanolic leave extract (APME) to induce anticancer immune response by activating NK cells was analysed via a co-culture experiment of the NK cells using breast cancer MDA-MB-231 cell lines. Subsequently, analysis of target cell deaths by a flow cytometric analysis was conducted followed by evaluation of cytokines, interleukin-2 (IL-2) and interferon-gamma (IFN-γ) levels. Degranulation of the cytotoxic granules was determined by quantifying perforin (PRF-1) and granzyme B (GzmB) using ELISA. APME activates NK cells obtained from healthy donors since the stimulated NK cells can induce apoptosis in target cells in-vitro with increased IFN-γ and PRF-1 levels seen. The findings indicate the ability of A. precatorius leaves extract to stimulate NK cells obtained from healthy donors and trigger its cytotoxicity in MDA-MB-231 cells.
References
Hu W, Wang G, Huang D, Sui M, Xu Y. Cancer immunotherapy based on natural killer cells: current progress and new opportunities. Front Immunol. 2019;10:1205. DOI: https://doi.org/10.3389/fimmu.2019.01205
O’Sullivan TE, Sun JC, Lanier LL. Natural killer cell memory. Immunity. 2015;43:634–645. DOI: https://doi.org/10.1016/j.immuni.2015.09.013
Grossenbacher SK, Canter RJ, Murphy WJ. Natural killer cell immunotherapy to target stem-like tumor cells. J Immunother Cancer. 2016;4:1–3. DOI: https://doi.org/10.1186/s40425-016-0124-2
Grudzien M, Rapak A. Effect of natural compounds on NK cell activation. J Immunol Res. 2018;2018:1–10. DOI: https://doi.org/10.1155/2018/4868417
Sconocchia G, Eppenberger S, Spagnoli GC, Tornillo L, Droeser R, Caratelli S et al. NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology. 2014;3:e952197. DOI: https://doi.org/10.4161/21624011.2014.952197
Prager I, Watzl C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J Leukoc Biol. 2019;105:1319–1329. DOI: https://doi.org/10.1002/JLB.MR0718-269R
Leischner C, Burkard M, Pfeiffer MM, Lauer UM, Busch C, Venturelli S. Nutritional immunology: function of natural killer cells and their modulation by resveratrol for cancer prevention and treatment. Nutr J. 2015;15:1–12. DOI: https://doi.org/10.1186/s12937-016-0167-8
Gomez-Cadena A, Uruena C, Prieto K, Martinez-Usatorre A, Donda A, Barreto A et al. Immune-system-dependent anti-tumor activity of a plant-derived polyphenol-rich fraction in a melanoma mouse model. Cell Death Dis. 2016;7:e2243. DOI: https://doi.org/10.1038/cddis.2016.134
Lee HH, Cho H. Improved anti-cancer effect of curcumin on breast cancer cells by increasing the activity of natural killer cells. J Microbiol Biotechnol. 2018;28:874–882. DOI: https://doi.org/10.4014/jmb.1801.01074
Alamgeer, Younis W, Asif H, Sharif A, Riaz H, Bukhari IA et al. Traditional medicinal plants used for respiratory disorders in Pakistan: a review of the ethnomedicinal and pharmacological evidence. Chin Med. 2018;13:48. DOI: https://doi.org/10.1186/s13020-018-0204-y
Kuete V. Toxicological Survey of African Medicinal Plants. 1st ed. Amsterdam: Elsevier; 2014. DOI: https://doi.org/10.1016/C2013-0-15406-2
Ramnath V, Kuttan G, Kuttan R. Effect of abrin on cell-mediated immune responses in mice. Immunopharmacol Immunotoxicol. 2006;28:259–268. DOI: https://doi.org/10.1080/08923970600816764
Bhutia SK, Mallick SK, Maiti TK. In vitro immunostimulatory properties of Abrus lectin-derived peptides in tumor-bearing mice. Phytomedicine. 2009;16:776–782. DOI: https://doi.org/10.1016/j.phymed.2009.01.006
Ghosh D, Maiti TK. Immunomodulatory and anti-tumor activities of native and heat-denatured Abrus agglutinin. Immunobiology. 2007;212:589–599. DOI: https://doi.org/10.1016/j.imbio.2007.03.005
Wan-Ibrahim WS, Ismail N, Mohd-Salleh SF, Yajid AI, Wong MPK, Hashim MNM. Methanolic extract of Abrus precatorius promotes breast cancer MDA-MB-231 cell death by inducing cell cycle arrest at G0/G1 and upregulating Bax. Asian Pac J Trop Biomed. 2019;9:249–255. DOI: 10.4103/2221-1691.260397
Qiu F, Liang CL, Liu H, Zeng YQ, Hou S, Huang S et al. Impacts of cigarette smoking on immune responsiveness: up and down or upside down? Oncotarget. 2017;8:268–284. DOI: https://doi.org/10.18632/oncotarget.13613
Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest Suppl. 1968;97:77–89.
Bose A, Chakraborty K, Sarkar K, Goswami S, Chakraborty T, Pal S et al. Neem leaf glycoprotein induces perforin-mediated tumor cell killing by T and NK cells through differential regulation of IFN-γ signaling. J Immunother. 2009;32:42–53. DOI: 10.1097/CJI.0b013e31818e997d
Igarashi M, Miyazawa T. Growth inhibitory effect of conjugated linoleic acid on a human hepatoma cell line (HepG2) is induced by altered fatty acid metabolism, not lipid peroxidation. Biochim Biophys Acta Mol Cell Biol Lipids. 2001;1530:162–171. DOI: https://doi.org/10.1016/S1388-1981(00)00180-3
Ismail N, Abdullah H, Seidel V, Rotondo D. Human natural killer cell activation by luteolin from Brucea javanica leaves. J Cancer Res Exp Oncol. 2018;10:10–14. DOI: https://doi.org/10.5897/JCREO2012.012
Nishimura Y, Kumagai-Takei N, Lee S, Matsuzaki H, Yoshitome K, Otsuki T. A new method to determine natural killer cell activity without target cells. In: Otsuki T, editor. Natural Killer Cells. Tokyo: Springer; 2017. p.181–188. DOI: 10.5772/intechopen.71912
Surayot U, You S. Structural effects of sulfated polysaccharides from Codium fragile on NK cell activation and cytotoxicity. Int J Biol Macromol. 2017;98:117–124. DOI: https://doi.org/10.1016/j.ijbiomac.2017.01.108
Fu D, Geschwind JF, Karthikeyan S, Miller E, Kunjithapatham R, Wang Z et al. Metabolic perturbation sensitizes human breast cancer to NK-cell-mediated cytotoxicity by increasing MHC class I chain-related A/B expression. Oncoimmunology. 2015;4:e991228. DOI: https://doi.org/10.4161/2162402X.2014.991228
Shaffer TM, Aalipour A, Schürch CM, Gambhir SS. PET imaging of the natural killer cell activation receptor NKp30. J Nucl Med. 2020;61:1348–1354. DOI: https://doi.org/10.2967/jnumed.119.233163
Rudnicka K, Matusiak A, Chmiela M. CD25 (IL-2R) expression correlates with target-cell-induced cytotoxic activity and cytokine secretion in human natural killer cells. Acta Biochim Pol. 2015;62:1–7. DOI: http://dx.doi.org/10.18388/abp.2015_1152
Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R et al. Human breast cancer cells enhance self-tolerance by promoting evasion from NK-cell antitumor immunity. J Clin Invest. 2011;121:3609–3622. DOI: 0.1172/JCI45816
Shenouda MM, Gillgrass A, Nham T, Hogg R, Lee AJ, Chew MV et al. Ex vivo expanded natural killer cells from breast cancer patients and healthy donors are highly cytotoxic against breast cancer cell lines and patient-derived tumours. Breast Cancer Res. 2017;19:84. DOI: https://doi.org/10.1186/s13058-017-0867-9
Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D et al. Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood. 2002;99:3661–3667. DOI: https://doi.org/10.1182/blood.V99.10.3661
Pasero C, Gravis G, Granjeaud S, Guerin M, Thomassin-Piana J, Rocchi P et al. Highly effective NK cells are associated with good prognosis in metastatic prostate cancer. Oncotarget. 2015;6:14360–14373. DOI: https://doi.org/10.18632/oncotarget.3965
Floros T, Tarhini AA. Anticancer cytokines: biology and clinical effects of interferon-α2, interleukin-2, interleukin-15, interleukin-21 and interleukin-12. Semin Oncol. 2015;42:539–548. DOI: https://doi.org/10.1053/j.seminoncol.2015.05.015
Shpakova AP, Pavlova KS, Bulycheva TI. MTT-colorimetric method for detection of cytotoxic activity of human natural killer cells. Klin Lab Diagn. 2000;5:20–23.
Lu CC, Hsu YJ, Chang CJ, Lin CS, Martel J, Ojcius DM et al. Immunomodulatory properties of medicinal mushrooms: differential effects of water and ethanol extracts on NK-cell-mediated cytotoxicity. Innate Immun. 2016;22:522–533. DOI: https://doi.org/10.1177/1753425916661402
Mhatre S, Madkaikar M, Ghosh K, Desai M, Pujari V, Gupta M. Rapid flow cytometry-based cytotoxicity assay for evaluation of NK cell function. Indian J Exp Biol. 2014;52:97–102.
Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 2016;17:1025–1036. DOI: https://doi.org/10.1038/ni.3518
Li T, Niu M, Zhang W, Qin S, Zhou J, Yi M. CAR-NK cells for cancer immunotherapy: recent advances and future directions. Front Immunol. 2024;15:1–12. DOI: https://doi.org/10.3389/fimmu.2024.1361194
Li Q, Meng F, Yang L, García AMD, Parkhats M, Lee J et al. Metabolic reprogramming of tumors: induced immunosuppression and therapeutic prospects of nanoscale drug delivery systems. Mol Pharm. 2025;22:5193–5211. DOI: https://doi.org/10.1021/acs.molpharmaceut.5c00342
Kumar D, Tanwar R. Advancing NK cell therapies: expansion and activation for next-generation immunotherapy. Curr Cancer Ther Rev. 2025;21:1–9. DOI: https://doi.org/10.2174/0115733947383194250701073137
Yang Y, Liu Q, Shi X, Zheng Q, Chen L, Sun Y. Advances in plant-derived natural products for antitumor immunotherapy. Arch Pharm Res. 2021;44:987–1011. DOI: https://doi.org/10.1007/s12272-021-01355-1
Barshidi A, Ardeshiri K, Ebrahimi F, Alian F, Shekarchi AA, Hojjat-Farsangi M et al. Role of exhausted natural killer cells in the immunopathogenesis and treatment of leukemia. Cell Commun Signal. 2024;22:59. DOI: https://doi.org/10.1186/s12964-023-01428-2
Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6:S11–S14. DOI: 10.1200/JCO.1999.17.7.2105
Sharma R, Das A. IL-2 mediates NK-cell proliferation but not hyperactivity. Immunol Res. 2018;66:151–157. DOI: https://doi.org/10.1007/s12026-017-8982-3
Granucci F, Vizzardelli C, Pavelka N, Feau S, Persico M, Virzi E et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol. 2001;2:882–888. DOI: https://doi.org/10.1038/ni0901-882
Gaffen SL. Signaling domains of the interleukin-2 receptor. Cytokine. 2001;14:63–77. DOI: https://doi.org/10.1006/cyto.2001.0862
Malek TR. The biology of interleukin-2. Annu Rev Immunol. 2008;26:453–479. DOI: https://doi.org/10.1146/annurev.immunol.26.021607.090357
Mah AY, Cooper MA. Metabolic regulation of natural killer cell IFN-γ production. Crit Rev Immunol. 2016;36:1–18. DOI: 10.1615/CritRevImmunol.2016017387
Björkström NK, Ljunggren HG, Michaelsson J. Emerging insights into natural killer cells in human peripheral tissues. Nat Rev Immunol. 2016;16:310–320. DOI: https://doi.org/10.1038/nri.2016.34
Wang R, Jaw JJ, Stutzman NC, Zou Z, Sun PD. Natural killer cell-produced IFN-γ and TNF-α induce target cell cytolysis through up-regulation of ICAM-1. J Leukoc Biol. 2012;91:299–309. DOI: https://doi.org/10.1189/jlb.0611308
Spicer BA, Conroy PJ, Law RHP, Voskoboinik I, Whisstock JC. Perforin: a key (shaped) weapon in the immunological arsenal. Semin Cell Dev Biol. 2017;72:117–123. DOI: https://doi.org/10.1016/j.semcdb.2017.07.033
Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015;15:388–400. DOI: https://doi.org/10.1038/nri3839
Fehniger TA, Cooper MA. Harnessing NK-cell memory for cancer immunotherapy. Trends Immunol. 2016;37:877–888. DOI: 10.1016/j.it.2016.09.005
Capuano C, Pighi C, Battella S, Santoni A, Palmieri G, Galandrini R. Memory NK-cell features exploitable in anticancer immunotherapy. J Immunol Res. 2019;2019:1–10. DOI: https://doi.org/10.1155/2019/8795673
Martinvalet D. Mitochondrial entry of cytotoxic proteases: a new insight into the granzyme B cell death pathway. Oxid Med Cell Longev. 2019;2019:1–12. DOI: https://doi.org/10.1155/2019/9165214
Afonina IS, Cullen SP, Martin SJ. Cytotoxic and non-cytotoxic roles of the CTL/NK protease granzyme B. Immunol Rev. 2010;235:105–116. DOI: https://doi.org/10.1111/j.0105-2896.2010.00908.x
McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2015;7:a026716. DOI: 10.1101/cshperspect.a008656
Madakkannu B, Ravichandran R. In vivo immunoprotective role of Indigofera tinctoria and Scoparia dulcis aqueous extracts against chronic noise stress-induced immune abnormalities in Wistar rats. Toxicol Rep. 2017;4:484–493. DOI: https://doi.org/10.1016/j.toxrep.2017.09.001
Diandong H, Feng G, Zaifu L, Helland T, Weixin F, Liping C. Sea buckthorn (Hippophae rhamnoides L.) oil protects against chronic stress-induced inhibitory function of natural killer cells in rats. Int J Immunopathol Pharmacol. 2016;29:76–83. DOI: https://doi.org/10.1177/0394632015619939
Ayyappan S, Na A, Jayakumar AN, Jinkala S. Fatal poisoning due to consumption of crushed Abrus precatorius seeds: an autopsy case report. Forensic Sci Med Pathol. 2025;21:763–767. DOI: https://doi.org/10.1007/s12024-024-00880-x
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Wan Suriyani Wan-Ibrahim, Norzila Ismail, Siti Farhanah Mohd-Salleh, Rohimah Mohamud, Wan Zainira Wan Zain, Hua Gan, John Ogbaji Igoli
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
