Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Naringenin-induced Oral Cancer Cell Apoptosis Via ROS-mediated Bid and Bcl-xl Signaling Pathway

Author(s): YuYe Du, Jia Lai, Jingyao Su, Jiali Li, Chuqing Li, Bing Zhu and Yinghua Li*

Volume 24, Issue 6, 2024

Published on: 13 November, 2023

Page: [668 - 679] Pages: 12

DOI: 10.2174/0115680096267430231023091521

Abstract

Background: Oral cancer is a malignant tumor with a high impact and poor prognosis. Naringenin, a flavonoid found in citrus fruits and its anti-inflammatory and antioxidant properties offer potential therapeutic benefits. However, limited studies have been conducted on the impact of naringenin on human tongue carcinoma CAL-27 cells. This study aims to elucidate the correlation between naringenin and tongue cancer, thereby identifying a potential therapeutic candidate for drug intervention against tongue cancer.

Methods: The effect of naringenin on the apoptosis of CAL-27 cells and its mechanism were studied by cell counting kit-8, mitochondrial membrane potential assay with JC-1, Annexin V-- FITC apoptosis detection, cell cycle, and apoptosis analysis, Reactive Oxygen Species assay and Western blot.

Results: The results showed that naringenin significantly induced apoptosis in CAL-27 cells in a dose-dependent manner. Mechanistically, naringenin-induced apoptosis was mediated through the upregulation of Bid and downregulation of Bcl-xl, which led to increased generation of ROS.

Conclusion: The findings suggested that naringenin may represent a promising candidate for the treatment of oral cancer by inducing apoptotic cell death via modulation of the Bid and Bcl-xl signaling pathways.

« Previous
Graphical Abstract

[1]
Sun, L.; Kang, X.; Wang, C.; Wang, R.; Yang, G.; Jiang, W.; Wu, Q.; Wang, Y.; Wu, Y.; Gao, J.; Chen, L.; Zhang, J.; Tian, Z.; Zhu, G.; Sun, S. Single-cell and spatial dissection of precancerous lesions underlying the initiation process of oral squamous cell carcinoma. Cell Discov., 2023, 9(1), 28.
[http://dx.doi.org/10.1038/s41421-023-00532-4] [PMID: 36914617]
[2]
Liu, C.; Wang, M.; Zhang, H.; Li, C.; Zhang, T.; Liu, H.; Zhu, S.; Chen, J. Tumor microenvironment and immunotherapy of oral cancer. Eur. J. Med. Res., 2022, 27(1), 198.
[http://dx.doi.org/10.1186/s40001-022-00835-4] [PMID: 36209263]
[3]
Siddiqui, M.R.; Railkar, R.; Sanford, T.; Crooks, D.R.; Eckhaus, M.A.; Haines, D.; Choyke, P.L.; Kobayashi, H.; Agarwal, P.K. Targeting Epidermal Growth Factor Receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) expressing bladder cancer using combination photoimmunotherapy (PIT). Sci. Rep., 2019, 9(1), 2084.
[http://dx.doi.org/10.1038/s41598-019-38575-x] [PMID: 30765854]
[4]
Sacco, A.G.; Chen, R.; Worden, F.P.; Wong, D.J.L.; Adkins, D.; Swiecicki, P.; Chai-Ho, W.; Oppelt, P.; Ghosh, D.; Bykowski, J.; Molinolo, A.; Pittman, E.; Estrada, M.V.; Gold, K.; Daniels, G.; Lippman, S.M.; Natsuhara, A.; Messer, K.; Cohen, E.E.W. Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: An open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet Oncol., 2021, 22(6), 883-892.
[http://dx.doi.org/10.1016/S1470-2045(21)00136-4] [PMID: 33989559]
[5]
Yun, H.M.; Park, J.E.; Lee, J.Y.; Park, K.R. Latifolin, a natural flavonoid, isolated from the heartwood of dalbergia odorifera induces bioactivities through apoptosis, autophagy, and necroptosis in human oral squamous cell carcinoma. Int. J. Mol. Sci., 2022, 23(21), 13629.
[http://dx.doi.org/10.3390/ijms232113629] [PMID: 36362414]
[6]
Zhang, P.; Lai, Z.L.; Chen, H.F.; Zhang, M.; Wang, A.; Jia, T.; Sun, W.Q.; Zhu, X.M.; Chen, X.F.; Zhao, Z.; Zhang, J. Retraction Note: Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice. J. Exp. Clin. Cancer Res., 2022, 41(1), 197.
[http://dx.doi.org/10.1186/s13046-022-02409-y] [PMID: 35681210]
[7]
Li, J.; Fan, Y.; Zhang, Y.; Liu, Y.; Yu, Y.; Ma, M. Resveratrol induces autophagy and apoptosis in non-small-cell lung cancer cells by activating the NGFR-AMPK-mTOR pathway. Nutrients, 2022, 14(12), 2413.
[http://dx.doi.org/10.3390/nu14122413] [PMID: 35745143]
[8]
Hung, S.W.; Li, Y.; Chen, X. Green tea epigallocatechin-3-gallate regulates autophagy in male and female reproductive cancer. Front Pharmacol., 2022, 13, 906746.
[http://dx.doi.org/10.3389/fphar.2022.906746]
[9]
Zhang, B.; Wan, S.; Liu, H. Naringenin alleviates renal ischemia reperfusion injury by suppressing er stress-induced pyroptosis and apoptosis through activating Nrf2/HO-1 signaling pathway. Oxid Med Cell Longev., 2022, 2022, 5992436.
[http://dx.doi.org/10.1155/2022/5992436]
[10]
Li, C.; Gong, Z.; Tan, X. Considerations regarding the tumor-suppressor role of naringenin as a novel agent for the treatment of oral squamous cell carcinoma. Cancer Immunol. Immunother., 2023, 72(9), 3133-3134.
[http://dx.doi.org/10.1007/s00262-023-03452-0] [PMID: 37149552]
[11]
Lin, C.; Zeng, Z.; Lin, Y. Naringenin suppresses epithelial ovarian cancer by inhibiting proliferation and modulating gut microbiota. Phytomedicine., 2022, 106, 154401.
[http://dx.doi.org/10.1016/j.phymed.2022.154401]
[12]
Kawaguchi, S.; Kawahara, K.; Fujiwara, Y.; Ohnishi, K.; Pan, C.; Yano, H.; Hirosue, A.; Nagata, M.; Hirayama, M.; Sakata, J.; Nakashima, H.; Arita, H.; Yamana, K.; Gohara, S.; Nagao, Y.; Maeshiro, M.; Iwamoto, A.; Hirayama, M.; Yoshida, R.; Komohara, Y.; Nakayama, H. Naringenin potentiates anti-tumor immunity against oral cancer by inducing lymph node CD169-positive macrophage activation and cytotoxic T cell infiltration. Cancer Immunol. Immunother., 2022, 71(9), 2127-2139.
[http://dx.doi.org/10.1007/s00262-022-03149-w] [PMID: 35044489]
[13]
Chen, D.; Zheng, R.; Su, J.; Lai, J.; Chen, H.; Ning, Z.; Liu, X.; Zhu, B.; Li, Y. Inhibition of H1N1 influenza virus-induced apoptosis by ebselen through ROS-mediated ATM/ATR signaling pathways. Biol. Trace Elem. Res., 2023, 201(6), 2811-2822.
[http://dx.doi.org/10.1007/s12011-022-03369-2] [PMID: 35896885]
[14]
Liu, X.; Chen, D.; Su, J. Selenium nanoparticles inhibited H1N1 influenza virus-induced apoptosis by ROS-mediated signaling pathways. RSC Adv., 2022, 12(7), 3862-3870.
[http://dx.doi.org/10.1039/D1RA08658H]
[15]
Su, J.; Chen, D.; Zheng, R.; Liu, X.; Zhao, M.; Zhu, B.; Li, Y. Duvira antarctic polysaccharide inhibited h1n1 influenza virus-induced apoptosis through ROS mediated ERK and STAT-3 signaling pathway. Mol. Biol. Rep., 2022, 49(7), 6225-6233.
[http://dx.doi.org/10.1007/s11033-022-07418-w] [PMID: 35412176]
[16]
Chen, D.; Ning, Z.; Su, J. Inhibition of H1N1 by picochlorum sp. 122 via AKT and p53 signaling pathways. Food Sci Nutr., 2023, 11(2), 743-751.
[17]
Xu, T.; Lai, J.; Su, J. Inhibition of H3N2 influenza virus induced apoptosis by selenium nanoparticles with chitosan through ROS-mediated signaling pathways. ACS Omega., 2023, 8(9), 8473-8480.
[http://dx.doi.org/10.1021/acsomega.2c07575]
[18]
Jin, Y.; Li, Y.; Wang, L. Physicochemical characterization of a polysaccharide from Rosa roxburghii Tratt fruit and its antitumor activity by activating ROS mediated pathways. Curr Res Food Sci., 2022, 5, 1581-1589.
[http://dx.doi.org/10.1016/j.crfs.2022.09.016]
[19]
Li, Y.; Chen, D.; Su, J. Selenium-ruthenium complex blocks H1N1 influenza virus-induced cell damage by activating GPx1/TrxR1. Theranostics., 2023, 13(6), 1843.
[20]
Rehfeldt, S.C.H.; Laufer, S.; Goettert, M.I. A highly selective in vitro JNK3 inhibitor, FMU200, restores mitochondrial membrane potential and reduces oxidative stress and apoptosis in SH-SY5Y cells. Int. J. Mol. Sci., 2021, 22(7), 3701.
[http://dx.doi.org/10.3390/ijms22073701] [PMID: 33918172]
[21]
Kumar, R.; Saneja, A.; Panda, A. K. An annexin V-FITC-propidium iodide-based method for detecting apoptosis in a non-small cell lung cancer cell line. Methods Mol Biol., 2021, 2279, 213-223.
[http://dx.doi.org/10.1007/978-1-0716-1278-1_17]
[22]
Banach, M.; Juranek, J.K.; Zygulska, A.L. Chemotherapy-induced neuropathies-a growing problem for patients and health care providers. Brain Behav., 2017, 7(1), e00558.
[http://dx.doi.org/10.1002/brb3.558] [PMID: 28127506]
[23]
Patritti Cram, J.; Wu, J.; Coover, R. A. P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis. Elife., 2022, 2011, 11.
[http://dx.doi.org/10.7554/eLife.73511]
[24]
Lenze, N.R.; Farquhar, D.R.; Dorismond, C.; Sheth, S.; Zevallos, J.P.; Blumberg, J.; Lumley, C.; Patel, S.; Hackman, T.; Weissler, M.C.; Yarbrough, W.G.; Olshan, A.F.; Zanation, A.M. Age and risk of recurrence in oral tongue squamous cell carcinoma: Systematic review. Head Neck, 2020, 42(12), 3755-3768.
[http://dx.doi.org/10.1002/hed.26464] [PMID: 32914472]
[25]
Motallebi, M.; Bhia, M.; Rajani, H. F. Naringenin: A potential flavonoid phytochemical for cancer therapy. Life Sci., 2022, 305, 120752.
[http://dx.doi.org/10.1016/j.lfs.2022.120752]
[26]
Stabrauskiene, J.; Kopustinskiene, D.M.; Lazauskas, R.; Bernatoniene, J. Naringin and naringenin: Their mechanisms of action and the potential anticancer activities. Biomedicines, 2022, 10(7), 1686.
[http://dx.doi.org/10.3390/biomedicines10071686] [PMID: 35884991]
[27]
Slika, H.; Mansour, H.; Wehbe, N. Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed Pharmacother., 2022, 146, 112442.
[http://dx.doi.org/10.1016/j.biopha.2021.112442]
[28]
Bergandi, L.; Mungo, E.; Morone, R. Hyperglycemia promotes chemoresistance through the reduction of the mitochondrial DNA damage, the Bax/Bcl-2 and Bax/Bcl-XL ratio, and the cells in Sub-G1 phase due to antitumoral drugs induced-cytotoxicity in human colon adenocarcinoma cells. Front Pharmacol., 2018, 9, 866.
[http://dx.doi.org/10.3389/fphar.2018.00866]
[29]
Schmitt, E.; Sané, A.T.; Steyaert, A.; Cimoli, G.; Bertrand, R. The Bcl-xL and Bax-alpha control points: Modulation of apoptosis induced by cancer chemotherapy and relation to TPCK-sensitive protease and caspase activation. Biochem. Cell Biol., 1997, 75(4), 301-314.
[PMID: 9493953]
[30]
Wang, Y.; Mandal, A.K.; Son, Y.O. Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane. Toxicol Appl Pharmacol., 2018, 353, 23-30.
[http://dx.doi.org/10.1016/j.taap.2018.06.003]
[31]
Setoguchi, K.; Cui, L.; Hachisuka, N. Antisense oligonucleotides targeting Y-box binding protein-1 inhibit tumor angiogenesis by downregulating Bcl-xL-VEGFR2/-tie axes. Mol Ther Nucleic Acids., 2017, 9, 170-181.
[http://dx.doi.org/10.1016/j.omtn.2017.09.004]
[32]
Hwang, K.E.; Kim, H.J.; Song, I.S.; Park, C.; Jung, J.W.; Park, D.S.; Oh, S.H.; Kim, Y.S.; Kim, H.R. Salinomycin suppresses TGF-β1-induced EMT by down-regulating MMP-2 and MMP-9 via the AMPK/SIRT1 pathway in non-small cell lung cancer. Int. J. Med. Sci., 2021, 18(3), 715-726.
[http://dx.doi.org/10.7150/ijms.50080] [PMID: 33437206]
[33]
Suraweera, C.D.; Banjara, S.; Hinds, M.G.; Kvansakul, M. Metazoans and intrinsic apoptosis: An evolutionary analysis of the Bcl-2 family. Int. J. Mol. Sci., 2022, 23(7), 3691.
[http://dx.doi.org/10.3390/ijms23073691] [PMID: 35409052]
[34]
Singh, S.; Barnes, C.A.; D’Souza, J.S.; Hosur, R.V.; Mishra, P. Curcumin, a potential initiator of apoptosis via direct interactions with Bcl-xL and Bid. Proteins, 2022, 90(2), 455-464.
[http://dx.doi.org/10.1002/prot.26238] [PMID: 34528298]
[35]
Edlich, F. BCL-2 proteins and apoptosis: Recent insights and unknowns. Biochem. Biophys. Res. Commun., 2018, 500(1), 26-34.
[http://dx.doi.org/10.1016/j.bbrc.2017.06.190] [PMID: 28676391]

© 2024 Bentham Science Publishers | Privacy Policy