Chrysin protects neuronal cells against carboplatin exposure-induced apoptosis and oxidative damage
Year 2025,
Volume: 17 Issue: 1, 1237 - 1244, 27.02.2025
Adnan Ayna
,
Sevda Sağ
,
İbrahim Bayav
,
Ekrem Darendelioğlu
Abstract
Chemotherapy drugs such as carboplatin are commonly used to treat various cancers, including testicular, lung, and ovarian cancer. Although carboplatin primarily targets cancer cells, it can also damage healthy cells, including neurons, leading to potential adverse effects. Notably, some side effects of carboplatin therapy are associated with nerve cells and the nervous system. The aim of our study was to investigate the potential protective effects of chrysin (Chr) against carboplatin-induced toxicity in SH-SY5Y neuronal cells. In this study, the ameliorative effects of Chr on carboplatin-induced cellular toxicity were evaluated through cell viability assays, lipid peroxidation (LPO) analysis to assess antioxidant capacity, TUNEL assay, immunohistochemistry (IHC) staining, and western blotting to examine anti-apoptotic activities. The results indicated that Chr mitigates carboplatin toxicity in SH-SY5Y cells by reducing LPO levels and the expression of cytochrome c (Cyt c) and Bax, while increasing the expression of the anti-apoptotic protein Bcl-2. The study also demonstrated that carboplatin caused apoptosis by causing DNA strand breaks while Chr treatment alleviated these effects. These findings suggest that the use of antioxidants, particularly Chr, may diminish the apoptotic effects of carboplatin in SH-SY5Y cells and could provide insights into potential therapeutic strategies for mitigating cell damage caused by carboplatin.
Supporting Institution
Bingol University
Project Number
BAP-FEF.2021.009
Thanks
We are grateful to Bingöl University Department of Molecular Biology and Genetics Department for useful discussions and aloowing us to access laboratory equipments when needed.
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- Kelles M, Tan M, Kalcioglu MT, Toplu Y, Bulam N. (2014). The protective effect of Chrysin against cisplatin induced ototoxicity in rats. Indian J Otolaryngol Head Neck Surg. 66(4), 369-374. doi:10.1007/s12070-013-0695-x.
- Kikuchi H, Yuan B, Hu X, Okazaki M. (2019). Chemopreventive and anticancer activity of flavonoids and its possibility for clinical use by combining with conventional chemotherapeutic agents. Am J Clin Cancer Res. 9(8), 1517.
- Kucukler S, Benzer F, Yildirim S, Gur C, Kandemir FM, Bengu AS, Dortbudak, MB. (2020). Protective effects of chrysin against oxidative stress and inflammation induced by lead acetate in rat kidneys: A biochemical and histopathological approach. Biol Trace Elem Res. 1-14. doi:10.1007/s12011-020-02268-8.
- Li X, Jankovic J, Le W. (2011). Iron chelation and neuroprotection in neurodegenerative diseases. J Neural Transm. 118:473–7. doi:10.1007/s00702-010-0518-0.
- Luo S, Zhou L, Dai Y, Lu Y, Liu Q. (2018). Analysis of Cytotoxic Effects of Chemotherapeutic Agents for Gastrointestinal Cancer with Cell-based Impedance Biosensor. Sens. Mater. 30(9), 1977-1987.
- Ma Z, Xu L, Liu D, Zhang X, Di S, Li W, Yan X. (2020). Utilizing Melatonin to Alleviate Side Effects of Chemotherapy: A Potentially Good Partner for Treating Cancer with Ageing. Oxid Med Cell Longev. doi:10.1155/2020/6841581.
- Mani R, Natesan V. (2018). Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action. Phytochemistry. 145, 187-196. doi:10.1016/j.phytochem.2017.09.016.
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Anchoring Protein (AKAP) Pathways. Int J Mol Mol Sci. 20(13), 3271. doi:10.3390/ijms20133271.
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- Shooshtari M K, Sarkaki A, Mansouri SMT, Badavi M, Khorsandi L, Dehcheshmeh MG, Farbood Y. (2020). Protective effects of Chrysin against memory impairment, cerebral hyperemia and oxidative stress after cerebral hypoperfusion and reperfusion in rats. Metab Brain Dis. 35(2), 401-412. doi:10.1007/s11011-019-00527-9.
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- Taslimi P, Kandemir FM, Demir Y, İleritürk M, Temel Y, Caglayan C, Gulçin İ. (2019). The antidiabetic and anticholinergic effects of chrysin on cyclophosphamide‐induced multiple organ toxicity in rats: Pharmacological evaluation of some metabolic enzyme activities. J Biochem Mol Toxicol. 33(6), e22313. doi:10.1002/jbt.22313.
- Temel Y, Kucukler S, Yıldırım S, Caglayan C, Kandemir FM. (2020). Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 393, 325-337. doi:10.1007/s00210-019-01741-z.
- Temel Y, Çağlayan C, Ahmed BM, Kandemir FM, Çiftci M. (2021). The effects of chrysin and naringin on cyclophosphamide-induced erythrocyte damage in rats: biochemical evaluation of some enzyme activities in vivo and in vitro. Naunyn Schmiedebergs Arch Pharmacol. 394, 645-654. doi:10.1007/s00210-020-01987-y.
- Yousef MI, Khalil DK, Abdou H M. (2018). Neuro-and nephroprotective effect of grape seed proanthocyanidin extract against carboplatin and thalidomide through modulation of inflammation, tumor suppressor protein p53, neurotransmitters, oxidative stress and histology. Toxicol Rep. 5, 568-578. doi:10.1016/j.toxrep.2018.04.006.
- Zhivotosky, B., & Orrenius, S. (2001). Assessment of apoptosis and necrosis by DNA fragmentation and morphological criteria. Curr Protoc Cell Biol, 12(1), 18-3.
Year 2025,
Volume: 17 Issue: 1, 1237 - 1244, 27.02.2025
Adnan Ayna
,
Sevda Sağ
,
İbrahim Bayav
,
Ekrem Darendelioğlu
Project Number
BAP-FEF.2021.009
References
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- Adelusi OB, Etemadi Y, Akakpo JY, Ramachandran A, Jaeschke H. (2024). Effect of ferroptosis inhibitors in a murine model of acetaminophen‐induced liver injury. J Biochem Mol Toxicol. 38(8), e23791. doi:10.1002/jbt.23791.
- Albers JW, Chaudhry V, Cavaletti G, Donehower RC. (2014) Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. (3). doi: 10.1002/14651858.CD005228.pub4.
- Amptoulach S, Tsavaris N. (2011). Neurotoxicity caused by the treatment with platinum analogues. Chemother Res Pract. 2011. doi:10.1155/2011/843019.
- Avan A, Postma TJ, Ceresa C, Avan A, Cavaletti G, Giovannetti E, Peters GJ. (2015). Platinum-induced neurotoxicity and preventive strategies: past, present, and future. Oncologist. 20(4), 411. doi:10.1634/theoncologist.2014-0044.
- Aykutoglu G, Tartik M, Darendelioglu E, Ayna A, Baydas G. (2020). Melatonin and vitamin E alleviate homocysteine‐induced oxidative injury and apoptosis in endothelial cells. Mol Biol Rep. 47, 5285–5293. doi:10.1007/s11033-020-05607-z.
- Ayna A, Özbolat SN, Darendelioglu E. (2020). Quercetin, chrysin, caffeic acid and ferulic acid ameliorate cyclophosphamide-induced toxicities in SH-SY5Y cells. Mol Biol Rep. 47(11), 8535-8543. doi:10.1007/s11033-020-05896-4.
- Ayna A, Varan SN. (2023) Investigation of the Protective Effects of Chrysin Against Paclitaxel-Induced Oxidative Stress and Apoptosis in Human Neuronal SH-SY5Y Cells. Turkish Journal of Nature and Science. 12(4), 107-113. doi: 10.46810/tdfd.1375041.
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- Bayav I, Darendelioğlu E, Caglayan C. (2024). 18β‐Glycyrrhetinic acid exerts cardioprotective effects against BPA‐induced cardiotoxicity through antiapoptotic and antioxidant mechanisms. J Biochem Mol Toxicol. 38(2), e23655. doi:10.1002/jbt.23655.
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- Campos H M, da Costa M, da Silva Moreira LK, da Silva Neri HF, da Silva C R.B, Pruccoli L, Ghedini PC. (2022). Protective effects of chrysin against the neurotoxicity induced by aluminium: In vitro and in vivo studies. Toxicology. 465, 153033. doi:10.1016/j.tox.2021.153033.
- Carozzi VA, Canta A, Chiorazzi A. (2015). Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms?. Neurosci Lett. 596, 90-107. doi:10.1016/j.neulet.2014.10.014.
- Cavalier AN, Clayton Z, Wahl D, Seals D, LaRocca T. (2020). The Effects of Chemotherapeutic Agents and a Mitochondrial Antioxidant on the Brain Transcriptome and Cognitive Function. FASEB J. 34(S1), 1-1. doi:10.1096/fasebj.2020.34.s1.09524.
- Çelik H, Kandemir F M, Caglayan C, Özdemir S, Çomaklı S, Kucukler S, Yardım A. (2020). Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions. Mol Biol Rep. 47(3), 2023-2034. doi:10.1007/s11033-020-05302-z.
- Cheng CF, Juan SH, Chen JJ, Chao Y C, Chen HH, Lian WS, Lin H. (2008). Pravastatin attenuates carboplatin-induced cardiotoxicity via inhibition of oxidative stress associated apoptosis. Apoptosis. 13(7), 883. doi:10.1007/s10495-008-0214-9.
- Donzelli, E., Carfì, M., Miloso, M., Strada, A., Galbiati, S., Bayssas, M., ... & Tredici, G. (2004). Neurotoxicity of platinum compounds: comparison of the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y. J Neurooncol, 67, 65-73.
- Emre Kızıl H, Gür C, Ayna A, Darendelioğlu E, Küçükler S, Sağ S. (2023). Contribution of oxidative stress, apoptosis, endoplasmic reticulum stress and autophagy pathways to the ameliorative effects of hesperidin in NaF‐induced testicular toxicity. Chem Biodivers. 20(3), e202200982. doi:10.1002/cbdv.202200982.
- Focaccetti C, Bruno A, Magnani E, Bartolini D, Principi E, Dallaglio K, Albini A. (2015). Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PloS one. 10(2), e0115686. doi:10.1371/journal.pone.0115686.
- Glazer RI. (2019). Developments In Cancer Chemotherapy: Vol. 2. CRC Press.
- Gulcin İ. (2020). Antioxidants and antioxidant methods: an updated overview. Arch Toxicol. 1-65. doi:10.1007/s00204-020-02689-3.
- Ho G Y, Woodward N, Coward J I. (2016). Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies. Crit Rev Oncol Hematol. 102,37-46. doi:10.1016/j.critrevonc.2016.03.014.
- Husain K, Whitworth C, Somani SM, Rybak L P. (2001). Carboplatin-induced oxidative stress in rat cochlea. Hear Res. 159(1-2), 14-22. doi:10.1016/S0378-5955(01)00306-9.
- Kanat O, Ertas H, Caner B. (2017). Platinum-induced neurotoxicity: a review of possible mechanisms. World J Clin Oncol. 8(4), 329. doi: 10.5306/wjco.v8.i4.329.
- Kelles M, Tan M, Kalcioglu MT, Toplu Y, Bulam N. (2014). The protective effect of Chrysin against cisplatin induced ototoxicity in rats. Indian J Otolaryngol Head Neck Surg. 66(4), 369-374. doi:10.1007/s12070-013-0695-x.
- Kikuchi H, Yuan B, Hu X, Okazaki M. (2019). Chemopreventive and anticancer activity of flavonoids and its possibility for clinical use by combining with conventional chemotherapeutic agents. Am J Clin Cancer Res. 9(8), 1517.
- Kucukler S, Benzer F, Yildirim S, Gur C, Kandemir FM, Bengu AS, Dortbudak, MB. (2020). Protective effects of chrysin against oxidative stress and inflammation induced by lead acetate in rat kidneys: A biochemical and histopathological approach. Biol Trace Elem Res. 1-14. doi:10.1007/s12011-020-02268-8.
- Li X, Jankovic J, Le W. (2011). Iron chelation and neuroprotection in neurodegenerative diseases. J Neural Transm. 118:473–7. doi:10.1007/s00702-010-0518-0.
- Luo S, Zhou L, Dai Y, Lu Y, Liu Q. (2018). Analysis of Cytotoxic Effects of Chemotherapeutic Agents for Gastrointestinal Cancer with Cell-based Impedance Biosensor. Sens. Mater. 30(9), 1977-1987.
- Ma Z, Xu L, Liu D, Zhang X, Di S, Li W, Yan X. (2020). Utilizing Melatonin to Alleviate Side Effects of Chemotherapy: A Potentially Good Partner for Treating Cancer with Ageing. Oxid Med Cell Longev. doi:10.1155/2020/6841581.
- Mani R, Natesan V. (2018). Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action. Phytochemistry. 145, 187-196. doi:10.1016/j.phytochem.2017.09.016.
- Miyano K, Shiraishi S, Minami K, Sudo Y, Suzuki M, Yokoyama T, Uezono Y. (2019). Carboplatin enhances the activity of human transient receptor potential ankyrin 1 through the Cyclic AMP-Protein Kinase AA-Kinase
Anchoring Protein (AKAP) Pathways. Int J Mol Mol Sci. 20(13), 3271. doi:10.3390/ijms20133271.
- Özbolat SN, Ayna A. (2020). Chrysin suppresses HT-29 cell death induced by diclofenac through apoptosis and oxidative damage. Nutr Cancer. 1-10. doi:10.1080/01635581.2020.1801775.
- Shooshtari M K, Sarkaki A, Mansouri SMT, Badavi M, Khorsandi L, Dehcheshmeh MG, Farbood Y. (2020). Protective effects of Chrysin against memory impairment, cerebral hyperemia and oxidative stress after cerebral hypoperfusion and reperfusion in rats. Metab Brain Dis. 35(2), 401-412. doi:10.1007/s11011-019-00527-9.
- Simon HU, Haj-Yehia A, Levi-Schaffer F. (2000). Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 5(5), 415-418. doi:10.1023/A:1009616228304.
- Su L J, Zhang JH, Gomez H, Murugan R, Hong X, Xu D, Peng ZY. (2019). Reactive oxygen species‐induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019(1), 5080843.17. doi:10.1155/2019/5080843.
- Taslimi P, Kandemir FM, Demir Y, İleritürk M, Temel Y, Caglayan C, Gulçin İ. (2019). The antidiabetic and anticholinergic effects of chrysin on cyclophosphamide‐induced multiple organ toxicity in rats: Pharmacological evaluation of some metabolic enzyme activities. J Biochem Mol Toxicol. 33(6), e22313. doi:10.1002/jbt.22313.
- Temel Y, Kucukler S, Yıldırım S, Caglayan C, Kandemir FM. (2020). Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 393, 325-337. doi:10.1007/s00210-019-01741-z.
- Temel Y, Çağlayan C, Ahmed BM, Kandemir FM, Çiftci M. (2021). The effects of chrysin and naringin on cyclophosphamide-induced erythrocyte damage in rats: biochemical evaluation of some enzyme activities in vivo and in vitro. Naunyn Schmiedebergs Arch Pharmacol. 394, 645-654. doi:10.1007/s00210-020-01987-y.
- Yousef MI, Khalil DK, Abdou H M. (2018). Neuro-and nephroprotective effect of grape seed proanthocyanidin extract against carboplatin and thalidomide through modulation of inflammation, tumor suppressor protein p53, neurotransmitters, oxidative stress and histology. Toxicol Rep. 5, 568-578. doi:10.1016/j.toxrep.2018.04.006.
- Zhivotosky, B., & Orrenius, S. (2001). Assessment of apoptosis and necrosis by DNA fragmentation and morphological criteria. Curr Protoc Cell Biol, 12(1), 18-3.