Naringin: antitumor potential in silico and in vitro on bladder cancer cells

Authors

  • Débora Radicchi Universidade Federal de Ouro Preto, Programa de Pós-Graduação em Ciências Biológicas (CBIOL), Ouro Preto. Universidade Federal de Ouro Preto, Escola de Farmácia, Departamento de Análises Clínicas, Ouro Preto
  • André Melo Universidade Federal de Ouro Preto, Escola de Farmácia, Departamento de Análises Clínicas https://orcid.org/0000-0001-8650-0089
  • Ana Paula Lima Universidade Federal de Ouro Preto, Escola de Farmácia, Departamento de Análises Clínicas. https://orcid.org/0000-0003-0271-0519
  • Tamires Almeida Universidade Federal de Ouro Preto, Escola de Farmácia, Departamento de Análises Clínicas https://orcid.org/0000-0002-5584-3609
  • Gustavo Souza Universidade Federal de Ouro Preto, Programa de Pós-Graduação em Biotecnologia (PPGBIOTEC) https://orcid.org/0000-0002-1548-3274
  • Glenda da Silva Universidade Federal de Ouro Preto, Escola de Farmácia, Departamento de Análises Clínicas https://orcid.org/0000-0001-9751-3379

DOI:

https://doi.org/10.30827/ars.v63i2.22430

Keywords:

cell cycle progression, flavonoid, in silico, naringin, bladder cancer
Agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant number CNPq-310905/2020-6 - CNPq Research Productivity Scholarship), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance code 001), Universidade Federal de Ouro Preto (grant number 23109.000928/2020-33)

Abstract

Introduction: Urothelial carcinoma is a significant public health problem. Transitional cell carcinoma (TCC) is the most common subtype, accounting for approximately 90 % of all bladder cancers. Chemotherapeutic protocols have been studied, but some present high toxicity and low tolerability. Naringin is a polyphenolic compound found mainly in citrus fruits, which antitumor activity has been studied in several types of cancer. However, there is little information about naringin effects on bladder cancer. This study aimed to evaluate the antitumor potential of naringin in silico and in vitro using two bladder cancer cell lines

Method: In silico analysis was carried out by PASS Online software. In vitro, the effects of naringin treatment (12.5 - 400 µM) were evaluated regarding its cytotoxicity, clonogenic survival, morphological alterations, cell cycle progression, migration, and mutagenicity

Results: In silico analyses predicted antitumor activity through several mechanisms of action. In vitro results showed naringin presented cytotoxic effects, reduced the number of colonies, inhibited cell migration, and changed the morphology and cell cycle progression of the two cell lines evaluated. However, naringin did not present mutagenic effects.

Conclusions: Naringin has antiproliferative activity and is a promising candidate for bladder cancer treatment.

Downloads

Download data is not yet available.

References

Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021;144(8):1941-1953. doi: 10.1002/ijc.31937

Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder cancer. Nat Rev Dis Primers. 2017;3(17022):1-19. doi: 10.1038/nrdp.2017.22

Chang SS, Bochner BH, Chou R, Dreicer R, Kamat AM, Lerner SP, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline. J Urol. 2017;198(3):552-559. doi: 10.1016/j.juro.2017.04.086

Lin SR, Chang CH, Hsu CF, Tsai MJ, Cheng H, Leong MK, et al. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. Br J Pharmacol. 2020;177(6):1409-1423. doi: 10.1111/bph.14816

Dutta S, Mahalanobish S, Saha S, Ghosh S, Sil PC. Natural products: An upcoming therapeutic approach to cancer. Food Chem Toxicol. 2019;128:240-255. doi: 10.1016/j.fct.2019.04.012

Chen R, Qi QL, Wang MT, Li QY. Therapeutic potential of naringin: an overview. Pharm Biol. 2016;54(12):3203-3210. doi: 10.1080/13880209.2016.1216131

Ghanbari-Movahed M, Jackson G, Farzaei MH, Bishayee A. A systematic review of the preventive and therapeutic effects of naringin against human malignancies. Front Pharmacol. 2021;12:639840. doi: 10.3389/fphar.2021.639840

Kim DI, Lee SJ, Lee SB, Park K, Kim WJ, Moon SK. Requirement for Ras/Raf/ERK pathway in naringin-induced G1-cell-cycle arrest via p21WAF1 expression. Carcinogenesis. 2008;29(9):1701-1709. doi: 10.1016/j.prnil.2017.11.001

Pereira GLDC, Almeida TC, Seibert JB, Amparo TR, Soares RDOA, Rodrigues IV, et al. Antitumor effect of Cymbopogon densiflorus (Linneu) essential oil in bladder cancer cells. Nat Prod Res. 2020; 2:1-5. doi: 10.1080/14786419.2020.1747453

Da Silva GN, de Castro Marcondes JP, de Camargo EA, Junior GASP, Sakamoto-Hojo, Salvadori DMF. Cell cycle arrest and apoptosis in TP53 subtypes of bladder carcinoma cell lines treated with cisplatin and gemcitabine. Exp Biol Med (Maywood). 2010;235(7):814-824. doi: 10.1258/ebm.2010.009322

Lima APB, Almeida TC, Barros TMB, Rocha LCM, Garcia CCM, Da Silva GN. Toxicogenetic and antiproliferative effects of chrysin in urinary bladder cancer cells. Mutagenesis. 2020;1(5):1-11. doi: 10.1093/mutage/geaa021

Sávio ALV, Da Silva GN, Salvadori DMF. Inhibition of bladder cancer cell proliferation by allyl isothiocyanate (mustard essential oil). Mutat Res. 2015;771:29-35. doi: 10.1016/j.mrfmmm.2014.11.004

Da Silva GN, De Camargo EA, Salvadori DMF. Toxicogenomic activity of gemcitabine in two TP53-mutated bladder cancer cell lines: special focus on cell cycle-related genes. Mol Biol Rep. 2012;39(12):10373-10382. doi: 10.1007/s11033-012-1916-1

Almeida TC, Guerra CCC, De Assis BLG, Soares RDOA, Garcia CCM, Lima AAL, et al. Antiproliferative and toxicogenomic effects of resveratrol in bladder cancer cells with different TP53 status. Environ Mol Mutagen. 2019;60(8):740-751. doi: 10.1002/em.22297

Barros TMB, Lima APB, Almeida TC, Da Silva GN. Inhibition of urinary bladder cancer cell proliferation by silibinin. Environ Mol Mutagen. 2020;61(4):445-455. doi: 10.1002/em.22363

Fenech M. The in vitro micronucleus technique. Mutat Res. 2000;455(1-2):81-95. doi: 10.1016/s0027-5107(00)00065-8

Achary PGR. Applications of quantitative structure-activity relationships (QSAR) based virtual screening in drug design: A review. Mini Rev Med Chem. 2020;20(14):1375-1388. doi: 10.2174/1389557520666200429102334

Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516. doi: 10.1080/01926230701320337

Slee EA, Adrain C, Martin SJ. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem. 2001;276:7320-7326. doi: 10.1074/jbc.M008363200

Banjerdpongchai R, Wudtiwai B, Khawon P. Induction of human hepatocellular carcinoma HepG2 cell apoptosis by naringin. Asian Pac J Cancer Prev. 2016;17(7):3289-3294.

Tsuboi A, Ohsawa S, Umetsu D, Sando Y, Kuranaga E, Igaki T, et al. Competition for space is controlled by apoptosis-induced change of local epithelial topology. Curr Biol. 2018;28(13):2115-2128. doi: 10.1016/j.cub.2018.05.029

Xu X, Lai Y, Hua ZC. Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep. 2019;39(1):1-17. doi: 10.1042/BSR20180992

Munshi A, Hobbs M, Meyn RE. Clonogenic cell survival assay. Methods Mol Med. 2005;110:21-28. doi: 10.1385/1-59259-869-2:021

Tannock IF, Lee C. Evidence against apoptosis as a major mechanism for reproductive cell death following treatment of cell lines with anti-cancer drugs. Br J Cancer. 2001;84:100-105. doi: 10.1054/bjoc.2000.1538

Xu C, Huang X, Huang Y, Liu X, Wu M, Wang J, et al. Naringin induces apoptosis of gastric carcinoma cells via blocking the PI3K/AKT pathway and activating pro‑death autophagy. Mol Med Rep. 2021;24(5):772. doi: 10.3892/mmr.2021.12412

Lin R, Hu X, Chen S, Shi Q, Chen H. Naringin induces endoplasmic reticulum stress-mediated apoptosis, inhibits β-catenin pathway and arrests cell cycle in cervical cancer cells. Acta Biochim Pol. 2020;67(2):181-188. doi: 10.18388/abp.2020_5182

Li H, Yang B, Huang J, Xiang T, Yin X, Wan J, et al. Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting β-catenin signaling pathway. Toxicol Lett. 2013;220(3):219-228. doi: 10.1016/j.toxlet.2013.05.006

Walz S, Lorenzin F, Morton J, Wiese KE, Eyss BV, Herold S, et al. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature. 2014;511:483-487. doi: 10.1038/nature13473

Zhou J, Xia L, Zhang Y. Naringin inhibits thyroid cancer cell proliferation and induces cell apoptosis through repressing PI3K/AKT pathway. Pathol Res Pract. 2019;215(12):152707. doi: 10.1016/j.prp.2019.152707

Aroui S, Aouey B, Chtourou Y, Meunier AC, Fetoui H, Kenani A. Naringin suppresses cell metastasis and the expression of matrix metalloproteinases (MMP-2 and MMP-9) via the inhibition of ERK-P38-JNK signaling pathway in human glioblastoma. Chem Biol Interact. 2016;244:195-203. doi: 10.1016/j.cbi.2015.12.011

Ming H, Chuang Q, Jiashi W, Bin L, Guangbin W, Xianglu J. Naringin targets Zeb1 to suppress osteosarcoma cell proliferation and metastasis. Aging. 2018;10(12):4141-4151. doi: 10.18632/aging.101710

Tan TW, Chou YE, Yang WH, Hsu CJ, Fong YC, Tang CH. Naringin suppress chondrosarcoma migration through inhibition vascular adhesion molecule-1 expression by modulating miR-126. Int Immunopharmacol. 2014;22(1):107-114. doi: 10.1016/j.intimp.2014.06.029

Saleh M, Khalil M, Abdellateif MS, Ebeid E, Madney Y, Kandeel EZ. Role of matrix metalloproteinase MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP-1) in the clinical progression of pediatric acute lymphoblastic leukemia. Hematology. 2021;26(1):758-768. doi: 10.1080/16078454.2021.1978763

Zhu J, Li Y, Chen C, Ma J, Sun W, Tian Z, et al. NF-κB p65 overexpression promotes bladder cancer cell migration via FBW7-mediated degradation of RhoGDIα protein. Neoplasia. 2017;19(9):672-683. doi: 10.1016/j.neo.2017.06.002

Bacanli M, Başaran AA, Başaran N. The antioxidant and antigenotoxic properties of citrus phenolics limonene and naringin. Food Chem Toxicol. 2015;81:160-170. doi: 10.1016/j.fct.2015.04.01

Downloads

Published

2022-03-21

How to Cite

1.
Radicchi D, Melo A, Lima AP, Almeida T, Souza G, da Silva G. Naringin: antitumor potential in silico and in vitro on bladder cancer cells. Ars Pharm [Internet]. 2022 Mar. 21 [cited 2025 Oct. 1];63(2):132-43. Available from: https://revistaseug.ugr.es/index.php/ars/article/view/22430

Issue

Section

Original Articles