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DOI: 10.1055/a-2687-0870
Sinapic Acid Protects Mortality and Toxicity Induced by N-Ethyl-N-Nitrosourea, a Full Carcinogen Agent, in Mice
Authors
Funding Information
Ardabil University of Medical Sciences — http://dx.doi.org/10.13039/501100006662; IR.ARUMS.AEC.1400.031

Abstract
Purpose
We investigated, in vivo, the chemopreventive efficacy of sinapic acid, as a known radical scavenger and antioxidant on mortality and toxicity in a N-ethyl-N-nitrosourea (ENU)-induced chronic lymphocytic leukemia (CLL) model in mice.
Methods
Mice were divided into three groups: control (normal saline), ENU (80 mg/kg, i.p., single dose on day 31), and sinapic acid+ENU (pretreated with 30 mg/kg of sinapic acid, i.p., daily for 30 days, followed by 80 mg/kg of ENU). Body weight changes and mortality were monitored over 120 days. After this period, the animals were sacrificed, and lymphocytes, the target cells in CLL, were isolated and evaluated for various cellular parameters.
Results
Sinapic acid significantly (P<0.001) increased mouse survival up to 71%, delayed time of death, and prevented weight loss following ENU exposure. Additionally, sinapic acid inhibited the formation of reactive oxygen species (ROS) (P<0.001), lysosomal and mitochondrial dysfunction (P<0.001), and lipid peroxidation (P<0.05) in the isolated lymphocytes. These findings indicate a protective effect of sinapic acid against ENU-induced lethal toxicity.
Conclusion
This study confirms that sinapic acid may serve as a promising chemopreventive agent against carcinogenicity induced by alkylating agents, primarily through the inhibition of oxidative stress and lysosomal/mitochondrial dysfunction.
Publication History
Received: 08 June 2025
Accepted: 04 August 2025
Article published online:
08 September 2025
© 2025. Thieme. All rights reserved.
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References
- 1 Gold SA, Margulis V. Carcinogenic effects of nitrosodimethylamine (NDMA) contamination in ranitidine: defining the relationship with renal malignancies. JU Open Plus 2023; 1: e00053
- 2 Davies SM. Therapy-related leukemia associated with alkylating agents. Medical and Pediatric Oncology: The Official Journal of SIOP—International Society of Pediatric Oncology (Societé Internationale d’Oncologie Pédiatrique 2001; 36: 536-540
- 3 Friedman DL. 44 - Secondary cancers in cancer survivors. Supportive Oncology. Saint Louis: W.B. Saunders 2011; 456-463
- 4 Riazat-Kesh YJRA, Mascarenhas J, Zommer MB-N. ‘Secondary’acute lymphoblastic/lymphocytic leukemia-done playing second fiddle?. Blood Reviews 2023; 101070
- 5 Guillem V, Tormo M. Influence of DNA damage and repair upon the risk of treatment related leukemia. Leukemia & lymphoma 2008; 49: 204-217
- 6 Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes & cancer 2011; 2: 95-107
- 7 Qian Z, Joslin JM, Tennant TR. et al. Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia. Chemico-biological interactions 2010; 184: 50-57
- 8 Valentini CG, Fianchi L, Voso MT. et al. Incidence of acute myeloid leukemia after breast cancer. Mediterranean journal of hematology and infectious diseases 2011; 3: e2011069
- 9 Polychronakis I, Dounias G, Makropoulos V. et al. Work-related leukemia: a systematic review. Journal of occupational medicine and toxicology (London, England) 2013; 8: 14
- 10 Tsai RJ, Luckhaupt SE, Schumacher P. et al. Acute myeloid leukemia risk by industry and occupation. Leuk Lymphoma 2014; 55: 2584-2591
- 11 Armijo AL, Thongararm P, Fedeles BI. et al. Molecular origins of mutational spectra produced by the environmental carcinogen N-nitrosodimethylamine and SN1 chemotherapeutic agents. NAR cancer 2023; 5: zcad015
- 12 Nath P, Maiti D. A review of the mutagenic potential of N-ethyl-N-nitrosourea (ENU) to induce hematological malignancies. Journal of Biochemical and Molecular Toxicology 2022; 36: e23067
- 13 van Breda SG, Mathijs K, Sági-Kiss V. et al. Impact of high drinking water nitrate levels on the endogenous formation of apparent N-nitroso compounds in combination with meat intake in healthy volunteers. Environmental Health 2019; 18: 1-12
- 14 Chain, E.P.o.C.i.t.F. Schrenk D, Bignami M. et al. Risk assessment of N-nitrosamines in food. EFSA Journal 2023; 21: e07884
- 15 Dietrich M, Block G, Pogoda JM. et al. A review: dietary and endogenously formed N-nitroso compounds and risk of childhood brain tumors. Cancer Causes & Control 2005; 16: 619-635
- 16 Smith-Roe SL, Hobbs CA, Hull V. et al. Adopting duplex sequencing technology for genetic toxicity testing: A proof-of-concept mutagenesis experiment with N-ethyl-N-nitrosourea (ENU)-exposed rats. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 2023; 891: 503669
- 17 Godley LA, Larson RA. Therapy-related myeloid leukemia. Seminars in oncology 2008; 35: 418-429
- 18 Terracina S, Ferraguti G, Petrella C. et al. Characteristic Hallmarks of Aging and the Impact on Carcinogenesis. Current Cancer Drug Targets 2023; 23: 87-102
- 19 G, MS Swetha M, Keerthana CK. et al. Cancer Chemoprevention: A Strategic Approach Using Phytochemicals. Frontiers in pharmacology 2021; 12: 809308
- 20 Esmeeta E, Adhikary A, Dharshnaa S. et al. Plant-derived bioactive compounds in colon cancer treatment: An updated review. Biomedicine & Pharmacotherapy 2022; 153: 113384
- 21 Gavrilas LI, Cruceriu D, Mocan A. et al. Plant-Derived Bioactive Compounds in Colorectal Cancer: Insights from Combined Regimens with Conventional Chemotherapy to Overcome Drug-Resistance. Biomedicines 2022; 10
- 22 Aggarwal V, Tuli HS, Varol A. et al. Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements. Biomolecules 2019; 9
- 23 Nićiforović N, Abramovič H. Sinapic acid and its derivatives: natural sources and bioactivity. Comprehensive reviews in food science and food safety 2014; 13: 34-51
- 24 Chen C. Sinapic Acid and Its Derivatives as Medicine in Oxidative Stress-Induced Diseases and Aging. Oxidative medicine and cellular longevity 2016; 2016: 3571614
- 25 Fernandes Q, Inchakalody VP, Bedhiafi T. et al. Chronic inflammation and cancer; the two sides of a coin. Life Sciences 2023;
- 26 Pandi A, Kalappan VM. Mechanisms involved in the anticancer effects of sinapic acid. Bulletin of the National Research Centre 2022; 46: 1-9
- 27 Badr DA, Amer ME, Abd-Elhay WM. et al. Histopathological and genetic changes proved the anti-cancer potential of free and nano-capsulated sinapic acid. Applied Biological Chemistry 2019; 62: 1-10
- 28 Balaji C, Muthukumaran J, Nalini N. Chemopreventive effect of sinapic acid on 1,2-dimethylhydrazine-induced experimental rat colon carcinogenesis. Human & experimental toxicology 2014; 33: 1253-1268
- 29 Hu X, Geetha RV, Surapaneni KM. et al. Lung cancer induced by Benzo (A) Pyrene: ChemoProtective effect of sinapic acid in swiss albino mice. Saudi journal of biological sciences 2021; 28: 7125-7133
- 30 Aliyu A, Shaari MR, Ahmad Sayuti NS. et al. N-Ethyl-n-Nitrosourea induced Leukaemia in a mouse model through upregulation of vascular endothelial growth factor and evading apoptosis. Cancers 2020; 12: 678
- 31 Pari L, Mohamed Jalaludeen A. Protective role of sinapic acid against arsenic – Induced toxicity in rats. Chemico-biological interactions 2011; 194: 40-47
- 32 Silambarasan T, Manivannan J, Krishna Priya M. et al. Sinapic acid prevents hypertension and cardiovascular remodeling in pharmacological model of nitric oxide inhibited rats. PloS one 2014; 9: e115682
- 33 Soltani M, Zarei MH, Salimi A. et al. Mitochondrial protective and antioxidant agents protect toxicity induced by depleted uranium in isolated human lymphocytes. Journal of environmental radioactivity 2019; 203: 112-116
- 34 Salimi A, Roudkenar MH, Seydi E. et al. Chrysin as an anti-cancer agent exerts selective toxicity by directly inhibiting mitochondrial complex II and V in CLL B-lymphocytes. Cancer investigation 2017; 35: 174-186
- 35 Salimi A, Roudkenar MH, Sadeghi L. et al. Selective anticancer activity of acacetin against chronic lymphocytic leukemia using both in vivo and in vitro methods: key role of oxidative stress and cancerous mitochondria. Nutrition and cancer 2016; 68: 1404-1416
- 36 Aghvami M, Ebrahimi F, Zarei MH. et al. Matrine induction of ROS mediated apoptosis in human ALL B-lymphocytes via mitochondrial targeting. Asian Pacific journal of cancer prevention: APJCP 2018; 19: 555
- 37 Salimi A, Talatappe BS, Pourahmad J. Xylene induces oxidative stress and mitochondria damage in isolated human lymphocytes. Toxicological research 2017; 33: 233-238
- 38 Ellman GL. Tissue sulfhydryl groups. Archives of biochemistry and biophysics 1959; 82: 70-77
- 39 Yan M, Zhu W, Zheng X. et al. Effect of glutamate on lysosomal membrane permeabilization in primary cultured cortical neurons. Molecular Medicine Reports 2016; 13: 2499-2505
- 40 Baracca A, Sgarbi G, Solaini G. et al. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F0 during ATP synthesis. Biochimica et biophysica acta (BBA)-bioenergetics 2003; 1606: 137-146
- 41 Ezoe S. Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. International journal of environmental research and public health 2012; 9: 2444-2453
- 42 Swetha M, Keerthana C, Rayginia TP. et al. Cancer chemoprevention: A strategic approach using phytochemicals. Frontiers in pharmacology 2022; 12: 809308
- 43 Tebbi CK. Etiology of Acute Leukemia: A Review. Cancers (Basel) 2021; 13
- 44 Singh V, Khurana A, Navik U. et al. Apoptosis and pharmacological therapies for targeting thereof for cancer therapeutics. Sci 2022; 4: 15
- 45 Tang T, Yang Z-Y, Wang D. et al. The role of lysosomes in cancer development and progression. Cell & bioscience 2020; 10: 1-18
- 46 Udensi UK, Tchounwou PB. Dual effect of oxidative stress on leukemia cancer induction and treatment. Journal of Experimental & Clinical Cancer Research 2014; 33: 1-15
- 47 George S, Abrahamse H. Redox Potential of Antioxidants in Cancer Progression and Prevention. Antioxidants (Basel, Switzerland) 2020; 9
- 48 Kim GR, Lim KH. Cytoprotective effects of sinapic acid on human keratinocytes (HaCaT) against ultraviolet B. Biomedical Dermatology 2018; 2: 1-7
- 49 Puertas MJ, González-Sánchez M. Insertions of mitochondrial DNA into the nucleus—effects and role in cell evolution. Genome 2020; 63: 365-374
- 50 Hsu C-C, Tseng L-M, Lee H-C. Role of mitochondrial dysfunction in cancer progression. Experimental Biology and Medicine 2016; 241: 1281-1295
- 51 Gorvin CM, Ahmad BN, Stechman MJ. et al. An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2019; 34: 497-507
- 52 Rong Z, Tu P, Xu P. et al. The mitochondrial response to DNA damage. Frontiers in Cell and Developmental Biology 2021; 9: 669379
- 53 Boulghobra D, Grillet P-E, Laguerre M. et al. Sinapine, but not sinapic acid, counteracts mitochondrial oxidative stress in cardiomyocytes. Redox Biology 2020; 34: 101554
- 54 Shabani M, Jamali Z, Naserian A. et al. Maintenance of mitochondrial function by sinapic acid protects against tramadol-induced toxicity in isolated mitochondria obtained from rat brain. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2023: 889-897
- 55 Pandi A, Kalappan VM. Pharmacological and therapeutic applications of Sinapic acid—An updated review. Molecular Biology Reports 2021; 48: 3733-3745
- 56 Roy SJ, Stanely Mainzen Prince P. Protective effects of sinapic acid on lysosomal dysfunction in isoproterenol induced myocardial infarcted rats. Food and Chemical Toxicology 2012; 50: 3984-3989