Anticancer Potential of Hesperidin against HEp-2 Laryngeal Carcinoma Cell Line in Comparison to Doxorubicin


  • Sara Abd El Wahed Department of Oral Pathology, Faculty of Dentistry, British University, Cairo, Egypt
  • Nadia Fathy Hassabou Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, October 6 University, 6th of October City, Egypt
  • Mai Abdelhalim Hamouda Department of Oral Pathology, Faculty of Dentistry, Ahram Canadian University, 6th of October City, Egypt



Hesperidin, Doxorubicin, HEp-2, Apoptosis, Cell cycle arrest


BACKGROUND: Doxorubicin (DOX) is a drug that is frequently used to treat a variety of cancers. Unfortunately, in many situations, it is ineffective, and raising the dosage is restricted due to systemic toxicity. An important strategy to minimize the toxic effects of the above cited drug is to use co-adjuvant. A citrus flavonoid hesperidin (Hesp) has emerged as promising anticancer natural product and proved to be potent antioxidant agent. It suppresses cancer cell replicating by triggering apoptosis and cell cycle arrest.

AIM: The study’s goal was to investigate anticarcinogenic effects of Hesp in comparison with DOX against HEp-2 laryngeal carcinoma cell line.

MATERIALS AND METHODS: Five groups of HEp-2 cell line were included, two groups were subjected to Hesp and the other two groups were subjected to DOX, which was used as a reference drug, in addition to a control untreated group. Expression of Bcl-2 and p53 genes was evaluated. Furthermore, the cell cycle arrest and apoptotic induction were assessed.

RESULTS: Hesp exerted anti-proliferative effects against HEp-2 cells which increase in time dependent manner. Gene profile analysis revealed highly statistically significant decrease of anti-apoptotic Bcl-2 expression and highly statistically significant increase of tumor suppressor gene p53 expression (p ˂ 0.01 and p ˂ 0.0001, respectively) for both tested drugs.

CONCLUSIONS: Hesp proved potential anticancer effects with reducing cancer cell viability in HEp-2 cell line through cell cycle arrest and apoptotic mechanism. It could be used as a prodrug or coadjuvant in treatment of oral cancer.


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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. PMid:30207593 DOI:

Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-53. PMid:30350310 DOI:

Johnson DE, Burtness B, Leemans CR, Lui VW, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6(1):92. PMid:33243986 DOI:

Peller M, Katalinic A, Wollenberg B, Teudt IU, Meyer JE. Epidemiology of laryngeal carcinoma in Germany, 1998-2011. Eur Arch Otorhinolaryngol. 2016;273(6):1481-7. PMid:26879991 DOI:

Du L, Ma S, Wen X, Chai J, Zhou D. Oral squamous cell carcinoma cells are resistant to doxorubicin through upregulation of miR 221. Mol Med Rep. 2017;16(3):2659-67. PMid:28677788 DOI:

Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, et al. American cancer society guidelines on nutrition and physical activity for cancer prevention: Reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin. 2012;62(1):30-67. PMid:22237782 DOI:

Hassabou NF, Farag AF. Anticancer effects induced by artichoke extract in oral squamous carcinoma cell lines. J Egypt Natl Canc Inst. 2020;32(1):17. PMid:32372389 DOI:

Kim J, Jayaprakasha GK, Uckoo RM, Patil BS. Evaluation of chemopreventive and cytotoxic effect of lemon seed extracts on human breast cancer (MCF-7) cells. Food Chem Toxicol. 2012;50(2):423-30. PMid:22056335 DOI:

Robbins RJ. Phenolic acids in foods: An overview of analytical methodology. J Agric Food Chem. 2003;51(10):2866-87. PMid:12720366 DOI:

Wudtiwai B, Makeudom A, Krisanaprakornkit S, Pothacharoen P, Kongtawelert P. Anticancer activities of hesperidin via suppression of up-regulated programmed death-ligand 1 expression in oral cancer cells. Molecules. 2021;26(17):5345. PMid:34500779 DOI:

Lee CJ, Wilson L, Jordan MA, Nguyen V, Tang J, Smiyun G. Hesperidin suppressed proliferations of both human breast cancer and androgen-dependent prostate cancer cells. Phytother Res. 2010;24(Suppl 1): S15-9. PMid:19548283 DOI:

Febriansah R, Putri DD, Sarmoko, Nurulita NA, Meiyanto E, Nugroh AE. Hesperidin as a preventive resistance agent in MCF-7 breast cancer cells line resistance to doxorubicin. Asian Pac J Trop Biomed. 2014;4(3):228-33. PMid:25182442 DOI:

Banjerdpongchai R, Wudtiwai B, Khaw-On P, Rachakhom W, Duangnil N, Kongtawelert P. Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways. Tumour Biol. 2016;37(1):227-37. PMid:26194866 DOI:

Aggarwal V, Tuli HS, Thakral F, Singhal P, Aggarwal D, Srivastava S, et al. Molecular mechanisms of action of hesperidin in cancer: Recent trends and advancements. Exp Biol Med (Maywood). 2020;245(5):486-97. PMid:32050794 DOI:

Du GY, He SW, Zhang L, Sun CX, Mi LD, Sun ZG. Hesperidin exhibits in vitro and in vivo antitumor effects in human osteosarcoma MG-63 cells and xenograft mice models via inhibition of cell migration and invasion, cell cycle arrest and induction of mitochondrial-mediated apoptosis. Oncol Lett. 2018;16(5):6299-306. PMid:30405765 DOI:

Xia R, Sheng X, Xu X, Yu C, Lu H. Hesperidin induces apoptosis and G0/G1 arrest in human non-small cell lung cancer A549 cells. Int J Mol Med. 2018;41(1):464-72. PMid:29138795 DOI:

Yeh MH, Kao ST, Hung CM, Liu CJ, Lee KH, Yeh CC. Hesperidin inhibited acetaldehyde-induced matrix metalloproteinase-9 gene expression in human hepatocellular carcinoma cells. Toxicol Lett. 2009;184(3):204-10. PMid:19110045 DOI:

Buranaamnuay K. The MTT assay application to measure the viability of spermatozoa: A variety of the assay protocols. Open Vet J. 2021;11(2):251-69. PMid:34307082 DOI:

Kwan YP, Saito T, Ibrahim D, Al-Hassan FM, Oon CE, ChenY, et al. Evaluation of the cytotoxicity, cell-cycle arrest, and apoptotic induction by Euphorbia hirta in MCF-7 breast cancer cells. Pharm Biol. 2016;54(7):1223-36. PMid:26154521 DOI:

Deavall DG, Martin EA, Horner JM, Roberts R. Drug-induced oxidative stress and toxicity. J Toxicol. 2012;2012:645460. PMid:22919381 DOI:

Mileo AM, Miccadei S. Polyphenols as modulator of oxidative stress in cancer disease: New therapeutic strategies. Oxid Med Cell Longev. 2016;2016:6475624. DOI:

Rahman MS, Alam MB, Choi YH, Yoo JC. Anticancer activity and antioxidant potential of Aponogeton undulatus against ehrlich ascites carcinoma cells in Swiss albino mice. Oncol Lett. 2017;14(3):3169-76. PMid:28927062 DOI:

Neophytou CM, Trougakos IP, Erin N, Papageorgis P. Apoptosis deregulation and the development of cancer multi-drug resistance. Cancers. 2021;13(17):4363. PMid:34503172 DOI:

Khedr NF, Khalil RM. Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin. Tumour Biol. 2015;36(12):9267-75. DOI:

Kamaraj S, Anandakumar P, Jagan S, Ramakrishnan G, Periyasamy P, Asokkumar S, et al. Hesperidin inhibits cell proliferation and induces mitochondrial-mediated apoptosis in human lung cancer cells through down regulation of β-catenin/c-myc. Biocatal Agric Biotechnol. 2019;18:101065. DOI:

Alimbetov D, Askarova S, Umbayev B, Davis T, Kipling D. Pharmacological targeting of cell cycle, apoptotic and cell adhesion signaling pathways implicated in chemoresistance of cancer cells. Int J Mol Sci. 2018;19(6):1690. PMid:29882812 DOI:

Yumnam S, Park HS, Kim MK, Nagappan A, Hong GE, Lee HJ, et al. Hesperidin induces paraptosis like cell death in hepatoblastoma, HepG2 Cells: Involvement of ERK1/2 MAPK. PLoS One. 2014;9(6):e101321. PMid:24977707 DOI:

Nazari M, Ghorbani A, Hekmat-Doost A, Jeddi-Tehrani M, Zand H. Inactivation of nuclear factor-κB by citrus flavanone hesperidin contributes to apoptosis and chemo-sensitizing effect in ramos cells. Eur J Pharmacol. 2011;650(2-3):526-33. PMid:21044621 DOI:

Shahbazi R, Cheraghpour M, Homayounfar R, Nazari M, Nasrollahzadeh J, Davoodi SH. Hesperidin inhibits insulin-induced phosphoinositide 3-kinase/Akt activation in human pre-B cell line NALM-6. J Cancer Res Ther. 2018;14(3):503-8. PMid:29893306 DOI:

Hana R, Bawi B. Hesperidin inhibits angiogenesis, induces apoptosis, and suppresses laryngeal cancer cell metastasis. Ibnosina J Med Biomed Sci. 2018;10(5):169. DOI:

Sulaiman GM, Waheeb HM, Jabir MS, Khazaal SH, Dewir YH, Naidoo Y. Hesperidin loaded on gold nanoparticles as a drug delivery system for a successful biocompatible, anti-cancer, anti-inflammatory and phagocytosis inducer model. Sci Rep. 2020;10(1):9362. DOI:

Natarajan N, Thamaraiselvan R, Lingaiah H, Srinivasan P, Periyasamy BM. Effect of flavonone hesperidin on the apoptosis of human mammary carcinoma cell line MCF-7. Biomed Prev Nutr. 2011;1(3):207-15. DOI:

Vabeiryureilai M, Lalrinzuali K, Jagetia GC. Chemopreventive effect of hesperidin, a citrus bioflavonoid in two stage skin carcinogenesis in Swiss albino mice. Heliyon. 2019;5(10):e02521. PMid:31720442 DOI:




How to Cite

El Wahed SA, Hassabou NF, Hamouda MA. Anticancer Potential of Hesperidin against HEp-2 Laryngeal Carcinoma Cell Line in Comparison to Doxorubicin. Open Access Maced J Med Sci [Internet]. 2022 Jul. 30 [cited 2024 Mar. 5];10(A):1300-9. Available from: