Allium hookeri extracts inhibit cisplatin-induced apoptosis and inflammation in human kidney HEK-293 cells

  • Ha-Rin Moon Department of Food and Nutrition, Chonnam National University, Yongbong-ro, Buk-gu, Gwangju 61186, South Korea https://orcid.org/0000-0003-4219-4045
  • Wooje Lee Technology Innovation Research Division, World Institute of Kimchi, 86 Kimchi-ro, Nam-gu, Gwangju, Republic of Korea
  • Jung-Mi Yun Department of Food & Nutrition, Chonnam National University https://orcid.org/0000-0001-6044-0647
DOI: https://doi.org/10.29219/fnr.v69.10764
Keywords: Allium hookeri, cisplatin, apoptosis, inflammation, HEK-293

Abstract

Background: Cisplatin is widely utilized in the treatment of solid malignant tumors due to its potent anticancer effects through the inhibition of cell division. However, its clinical use is often limited by significant adverse effects, particularly nephrotoxicity. Recent research has focused on natural products as potential mitigators of cisplatin-induced kidney toxicity. Allium hookeri (A. hookeri), a traditional food and herbal medicine in Southeast Asia, is known for its antioxidant and anti-inflammatory properties. However, its protective effects against nephrotoxicity remain unclear.

Objective: This study aimed to investigate the protective effects of A. hookeri against cisplatin-induced nephrotoxicity in human embryonic kidney (HEK)-293 cells.

Methods: HEK-293 cells were treated with cisplatin (50 μM) with or without A. hookeri water extract (AHWE) and ethanol extract (AHEE) for 24 h. Cell viability was assessed using MTT assays, and nuclear morphology was examined through Hoechst 33342 staining. Intracellular reactive oxygen species (ROS) production was quantified using ROS detection assays, and nitric oxide (NO) production was measured through Griess reaction assays. Protein and mRNA expression levels were analyzed using western blotting and quantitative polymerase chain reaction (qPCR) techniques.

Results: Cisplatin treatment (50 μM) significantly increased ROS production compared to untreated cells within 24 h. Both AHWE and AHEE treatments markedly attenuated ROS generation. Additionally, AHWE and AHEE significantly inhibited NO production and downregulated the expression of inflammation-related genes. The treatments also suppressed mitogen-activated protein kinase (MAPK) protein expression. Pretreatment with AHWE and AHEE decreased the Bax/Bcl-2 expression ratio, demonstrating a dose-dependent inhibition of apoptotic features.

Conclusion: The findings suggest that A. hookeri exerts protective effects against cisplatin-induced kidney damage by modulating MAPK signaling, thereby reducing inflammation and apoptosis in HEK-293 cells. A. hookeri represents a promising therapeutic candidate for the prevention and treatment of nephrotoxicity.

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References


1.
Faria J, Ahmed S, Gerritsen KG, Mihaila SM, Masereeuw R. Kidney-based in vitro models for drug-induced toxicity testing. Arch Toxicol 2019; 93(12): 3397–418. doi: 10.1007/s00204-019-02598-0


2.
Al-Naimi MS, Rasheed HA, Hussien NR, Al-Kuraishy HM, Al-Gareeb AI. Nephrotoxicity: role and significance of renal biomarkers in the early detection of acute renal injury. J Adv Pharm Technol Res 2019; 10(3): 95–9. doi:10.4103/japtr.JAPTR_336_18


3.
Dobrek L. A synopsis of current theories on drug-induced nephrotoxicity. Life (Basel) 2023; 13(2): 325. doi: 10.3390/life13020325


4.
Arnesano F, Natile G. Mechanistic insight into the cellular uptake and processing of cisplatin 30 years after its approval by FDA. Coordin Chem Rev 2009; 253(15–16): 2070–81. doi: 10.1016/j.ccr.2009.01.028


5.
Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008; 73(9): 994–1007. doi: 10.1038/sj.ki.5002786


6.
Song KI, Park JY, Lee S, Lee D, Jang HJ, Kim SN, et al. Protective effect of tetrahydrocurcumin against cisplatin-induced renal damage: in vitro and in vivo studies. Planta Med 2015; 81(4): 286–91. doi: 10.1055/s-0035-1545696


7.
Mi XJ, Hou Jg, Wang Z, Han Y, Ren S, Hu JN, et al. The protective effects of maltol on cisplatin-induced nephrotoxicity through the AMPK-mediated PI3K/Akt and p53 signaling pathways. Sci Rep 2018; 8(1): 15922. doi: 10.1038/s41598-018-34156-6


8.
Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014; 740: 364–78. doi: 10.1016/j.ejphar.2014.07.025


9.
Nauffal M, Gabardi S. Nephrotoxicity of natural products. Blood Purif 2016; 41(1–3): 123–9. doi: 10.1159/000441268


10.
Chen YQ, Chen HY, Tang QQ, Li YF, Liu XS, Lu FH, et al. Protective effect of quercetin on kidney diseases: from chemistry to herbal medicines. Front Pharmacol 2022; 13: 968226. doi: 10.3389/fphar.2022.968226


11.
Zhong Y, Liu J, Sun D, Guo T, Yao Y, Xia X, et al. Dioscin relieves diabetic nephropathy via suppressing oxidative stress and apoptosis, and improving mitochondrial quality and quantity control. Food Funct 2022; 13(6): 3660–73. doi: 10.1039/d1fo02733f


12.
Zabad IEM, Amin MN, El-Shishtawy MM. Protective effect of vanillin on diabetic nephropathy by decreasing advanced glycation end products in rats. Life Sci 2019; 239: 117088. doi: 10.1016/j.lfs.2019.117088


13.
Rhyu DY, Park SH. Characterization of alkyl thiosulfinate in Allium hookeri root using HPLC-ESI-MS. J Korean Soc Appl Biol Chem 2013; 56(4): 457–9. doi: 10.1007/s13765-013-3069-x


14.
Choi JH, Kim SH, Lee EB, Kim JS, Jung JE, Jeong UY, et al. Anti-diabetic effects of Allium hookeri extracts prepared by different methods in type 2 C57BL/J-db/db mice. Pharmaceuticals 2022; 15(4): 486. doi: 10.3390/ph15040486


15.
Choi JH, Lee EB, Jang HH, Cha YS, Park YS, Lee SH. Allium hookeri extracts improve scopolamine-induced cognitive impairment via activation of the cholinergic system and anti-neuroinflammation in mice. Nutrients 2021; 13(8): 2890. doi: 10.3390/nu13082890


16.
Kima JE, Seo JH, Bae MS, Bae CS, Yoo JC, Bang MA, et al. Antimicrobial constituents from Allium hookeri root. Nat Prod Commun. 2016; 11(2): 237–8. doi: 10.1177/1934578X1601100226


17.
Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 2014; 20(7): 1126–67. doi: 10.1089/ars.2012.5149


18.
Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive oxygen species in metabolic and inflammatory signaling. Circ Res 2018; 122(6): 877–902. doi: 10.1161/CIRCRESAHA.117.311401


19.
Tavener SK, Jewell DE, Panickar KS. The increase in circulating levels of pro-inflammatory chemokines, cytokines, and complement C5 in Canines with impaired kidney function. Curr Issues Mol Biol 2022; 44(4): 1664–76. doi: 10.3390/cimb44040114


20.
Faubel S, Lewis EC, Reznikov L, Ljubanovic D, Hoke TS, Somerset H, et al. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney. J Pharmacol Exp Ther 2007; 322(1): 8–15. doi: 10.1124/jpet.107.119792


21.
Wang H, Xia W, Long G, Pei Z, Li Y, Wu M, et al. Isoquercitrin ameliorates cisplatin-induced nephrotoxicity via the inhibition of apoptosis, inflammation, and oxidative stress. Front Pharmacol 2020; 11: 599416. doi: 10.3389/fphar.2020.599416


22.
Tsuruya K, Ninomiya T, Tokumoto M, Hirakawa M, Masutani K, Taniguchi M, et al. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int 2003; 63(1): 72–82. doi: 10.1046/j.1523-1755.2003.00709.x


23.
Zhu X, Jiang X, Li A, Zhao Z, Li S. S-Allylmercaptocysteine attenuates cisplatin-induced nephrotoxicity through suppression of apoptosis, oxidative stress, and inflammation. Nutrients 2017; 9(2): 166. doi: 10.3390/nu9020166


24.
Marullo R, Werner E, Degtyareva N, Moore B, Altavilla G, Ramalingam SS, et al. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One. 2013; 8(11): e81162. doi: 10.1371/journal.pone.0081162


25.
Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J. The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front Oncol 2022; 12: 985363. doi: 10.3389/fonc.2022.985363


26.
Yue J, López JM. Understanding MAPK signaling pathways in apoptosis. Int J Mol Sci 2020; 21(7): 2346. doi: 10.3390/ijms21072346


27.
Brozovic A, Osmak M. Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett 2007; 251(1): 1–16. doi: 10.1016/j.canlet.2006.10.007


28.
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298(5600): 1911–12. doi: 10.1126/science.1072682


29.
Clark JS, Faisal A, Baliga R, Nagamine, Y, Arany I. Cisplatin induces apoptosis through the ERK–p66shc pathway in renal proximal tubule cells. Cancer Lett 2010; 297(2): 165–70. doi: 10.1016/j.canlet.2010.05.007


30.
Marletta MA. Nitric oxide synthase structure and mechanism. J Biol Chem 1993; 268(17): 12231–4. doi: 10.1016/S0021-9258(18)31375-9


31.
Zhang H, Sun SC. NF-κB in inflammation and renal diseases. Cell Biosci 2015; 5(1): 1–12. doi: 10.1186/s13578-015-0056-4


32.
Cassidy H, Radford R, Slyne J, O’Connell S, Slattery C, Ryan MP, et al. The role of MAPK in drug-induced kidney injury. J Signal Transduct 2012; 2012: 463617. doi: 10.1155/2012/463617


33.
Fang CY, Lou DY, Zhou LQ, Wang JC, Yang B, He QJ, et al. Natural products: potential treatments for cisplatin-induced nephrotoxicity. Acta Pharmacol Sinica 2021; 42(12): 1951–69. doi: 10.1038/s41401-021-00620-9


34.
Sahu BD, Kuncha M, Sindhura GJ, Sistla R. Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage. Phytomedicine 2013; 20(5): 453–60. doi: 10.1016/j.phymed.2012.12.001


35.
Kang KP, Park SK, Kim DH, Sung MJ, Jung YJ, Lee AS, et al. Luteolin ameliorates cisplatin-induced acute kidney injury in mice by regulation of p53-dependent renal tubular apoptosis. Nephrol Dial Transplant 2011; 26(3): 814–22. doi: 10.1093/ndt/gfq528


36.
Jiang M, Dong Z. Regulation and pathological role of p53 in cisplatin nephrotoxicity. J Pharmacol Exp Ther 2008; 327(2): 300–7. doi: 10.1124/jpet.108.139162


37.
Yoshikawa S, Taniguchi K, Sawamura H, Ikeda Y, Tsuji A, Matsuda S. Roles of reactive oxygen species and autophagy in the pathogenesis of cisplatin-induced acute kidney injury. Oxygen 2022; 2(3): 317–26. doi: 10.3390/oxygen2030022


38.
Sinenko SA, Starkova TY, Kuzmin AA, Tomilin AN. Physiological signaling functions of reactive oxygen species in stem cells: from flies to man. Front Cell Dev Biol 2021; 9: 714370. doi: 10.3389/fcell.2021.714370


39.
Mizutani H, Hotta S, Nishimoto A, Ikemura K, Miyazawa D, Ikeda Y, et al. Pirarubicin, an anthracycline anticancer agent, induces apoptosis through generation of hydrogen peroxide. Anticancer Res 2017; 37(11): 6063–9. doi: 10.21873/anticanres.12054


40.
Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, et al. Oxygen radicals and human disease. Ann Intern Med 1987; 107(4): 526–45. doi: 10.7326/0003-4819-107-4-526


41.
Chang KC, Liu PF, Chang CH, Lin YC, Chen YJ, Shu CW. The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases. Cell Biosci 2022; 12(1): 1. doi: 10.1186/s13578-021-00736-9


42.
Yu Y, Feng B, Yan L, Bi Z, Zhu G, Jiang F. Ruscogenin protects against cisplatin-induced apoptosis, inflammation, and oxidative stress of renal tubular epithelial cells. Trop J Pharm Res 2021; 20(6): 1159–64. doi: 10.4314/tjpr.v20i6.9


43.
Tusskorn O, Pansuksan K, Machana K. Borassus flabellifer L. crude male flower extracts alleviate cisplatin-induced oxidative stress in rat kidney cells. Asian Pac J Trop Biomed. 2021; 11(12): 81–8. doi: 10.4103/2221-1691.303607


44.
Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 2011; 30(1): 1–14. doi: 10.1186/1756-9966-30-87


45.
Verzola D, Gandolfo MT, Ferrario F, Rastaldi MP, Villaggio B, Gianiorio F, et al. Apoptosis in the kidneys of patients with type II diabetic nephropathy. Kidney Int 2007; 72(10): 1262–72. doi: 10.1038/sj.ki.5002531


46.
Allen S, Sotos J, Sylte M, Czuprynski C. Use of Hoechst 33342 staining to detect apoptotic changes in bovine mononuclear phagocytes infected with Mycobacterium avium subsp. paratuberculosis. Clin Diagn Lab Immunol 2001; 8(2): 460–4. doi: 10.1128/CDLI.8.2.460-464.2001


47.
Fan X, Wei W, Huang J, Peng L, Ci X. Daphnetin attenuated cisplatin-induced acute nephrotoxicity with enhancing antitumor activity of cisplatin by upregulating SIRT1/SIRT6-Nrf2 pathway. Front Pharmacol. 2020; 11: 579178. doi: 10.3389/fphar.2020.579178


48.
Shamas-Din A, Kale J, Leber B, Andrews DW. Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol 2013; 5(4): a008714. doi: 10.1101/cshperspect.a008714


49.
Hussar P. Apoptosis regulators Bcl-2 and Caspase-3. Encyclopedia 2022; 2(4): 1624–36. doi: 10.3390/encyclopedia2040111


50.
Chen X, Wei W, Li Y, Huang J, Ci X. Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem Biol Interact 2019; 308: 269–78. doi: 10.1016/j.cbi.2019.05.040


51.
Zhou Yd, Hou Jg, Yang G, Jiang S, Chen C, Wang Z, et al. Icariin ameliorates cisplatin-induced cytotoxicity in human embryonic kidney 293 cells by suppressing ROS-mediated PI3K/Akt pathway. Biomed Pharmacother 2019; 109: 2309–17. doi: 10.1016/j.biopha.2018.11.108


52.
Rodríguez-García ME, Quiroga AG, Castro J, Ortiz A, Aller P, Mata F. Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells. Toxicol Sci 2009; 111(2): 413–23. doi: 10.1093/toxsci/kfp145


53.
Achkar IW, Abdulrahman N, Al-Sulaiti H, Joseph JM, Uddin S, Mraiche F. Cisplatin based therapy: the role of the mitogen activated protein kinase signaling pathway. J Transl Med. 2018; 16(1): 1–12. doi: 10.1186/s12967-018-1471-1


54.
Ma F, Liu J, Nikolic-Paterson DJ. The role of stress-activated protein kinase signaling in renal pathophysiology. Braz J Med Biol Res 2009; 42(1): 29–37. doi: 10.1590/s0100-879x2008005000049


55.
Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 2005; 289(1): F166–74. doi: 10.1152/ajprenal.00401.2004


56.
Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 1999; 19(8): 5800–10. doi: 10.1128/MCB.19.8.5800


57.
Ma Z, Liu Z, Wang Z, Ren S, Tang S, Wang Yp, et al. Supplementation of American ginseng berry extract mitigated cisplatin-evoked nephrotoxicity by suppressing ROS-mediated activation of MAPK and NF-κB signaling pathways. Food Chem Toxicol 2017; 110: 62–73. doi: 10.1016/j.fct.2017.10.006


58.
Diomede L, Rigacci S, Romeo M, Stefani M, Salmona M. Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit. PLoS One 2013; 8(3): e58893. doi: 10.1371/journal.pone.0058893


59.
Rajasundari A, Pays L, Mehlen P, Ramesh G. Netrin-1 overexpression in kidney proximal tubular epithelium ameliorates cisplatin nephrotoxicity. Lab Invest 2011; 91(12): 1717–26. doi: 10.1038/labinvest.2011.126


60.
Meng XM, Li HD, Wu WF, Ming-Kuen Tang P, Ren GL, Gao L, et al. Wogonin protects against cisplatin-induced acute kidney injury by targeting RIPK1-mediated necroptosis. Lab Invest 2018; 98(1): 79–94. doi: 10.1038/labinvest.2017.115


61.
Yu X, Meng X, Xu M, Zhang X, Zhang Y, Ding G, et al. Celastrol ameliorates cisplatin nephrotoxicity by inhibiting NF-κB and improving mitochondrial function. EBioMedicine 2018; 36: 266–80. doi: 10.1016/j.ebiom.2018.09.031


62.
Ramesh G, Reeves WB. TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002; 110(6): 835–42. doi: 10.1172/JCI15606


63.
Pei Z, Wu M, Yu H, Long G, Gui Z, Li X, et al. Isoliquiritin ameliorates cisplatin-induced renal proximal tubular cell injury by antagonizing apoptosis, oxidative stress and inflammation. Front Med (Lausanne) 2022; 9: 873739. doi: 10.3389/fmed.2022.873739
Published
2025-06-05
How to Cite
Moon , H.-R., Lee , W., & Yun , J.-M. (2025). Allium hookeri extracts inhibit cisplatin-induced apoptosis and inflammation in human kidney HEK-293 cells. Food & Nutrition Research, 69. https://doi.org/10.29219/fnr.v69.10764
Issue
Vol 69 (2025)
Section
Original Articles
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