Apigeninin Radyasyona Bağlı Özofagus Hasarına Karşı Koruyucu Etkileri: Sıçanlarda Yapılan Deneysel Bir Çalışma

Abstract

Amaç: Radyoterapi (RT), yemek borusu, akciğer, baş-boyun ve mediasten kanserleri için temel bir tedavi yöntemidir. Ancak, radyasyona bağlı özofajit gibi ciddi yan etkileri nedeniyle etkinliği genellikle sınırlıdır ve bu durum tedavi sürekliliğini ve hastanın yaşam kalitesini olumsuz etkileyebilir. Bu çalışma, anti-inflamatuar ve antioksidan özellikleri kanıtlanmış doğal bir flavonoid olan Apigenin'in deneysel bir sıçan modelinde RT kaynaklı özofagus hasarına karşı potansiyel koruyucu rolünü değerlendirmeyi amaçlamaktadır. Gereç ve Yöntemler: Toplam 40 sıçan dört gruba ayrıldı: RT, RT+Apigenin+Dimetil sülfoksit (DMSO), RT+DMSO ve Apigenin+DMSO. Uygun gruplara servikal bölgeye tek doz 16 Gy RT uygulandı. Doku hasarı ve inflamasyonu değerlendirmek için histopatolojik inceleme ve tümör nekroz faktörü-alfa (TNF-α) ekspresyon analizi kullanıldı. Bulgular: Histopatolojik incelemede, RT grubunda özofagus dokusunda belirgin hiperemi, mikrohemorajiler, erozyonlar ve hafif düzeyde inflamatuar yanıt izlendi (p<0,001). Buna karşın, RT+Apigenin+DMSO grubunda söz konusu histopatolojik bulgularda anlamlı derecede bir azalma gözlendi (p<0,001). İmmunohistokimyasal analizler sonucunda, RT grubunun özofagus epitel hücrelerinde TNF-α ekspresyonunun anlamlı şekilde arttığı tespit edildi (p<0,001). RT+Apigenin+DMSO grubunda ise TNF-α düzeylerinde belirgin bir azalma saptandı (p<0,001). Sonuç: Bu çalışma, Apigeninin RT kaynaklı özofajiyal toksisiteye karşı potansiyel bir radyoprotektif ajan olarak işlev görebileceğini göstermektedir ve histopatolojik ve immünohistokimyasal bulgular bu koruyucu etkisini desteklemektedir. Klinik uygulamaya aktarılabilirliğini doğrulamak için ise daha ileri klinik öncesi ve kontrollü klinik çalışmalara ihtiyaç vardır.

Keywords

• Apigenin
• Radyoterapi
• Özofajit

Protective Effects of Apigenin against Radiation-Induced Esophageal Injury: An Experimental Study in Rats

Abstract

Aim: Radiotherapy (RT) is a cornerstone treatment for cancers of the esophagus, lung, head and neck, and mediastinum. However, its efficacy is often limited by serious side effects, such as radiation-induced esophagitis, which can compromise treatment continuity and patient quality of life. This study aimed to evaluate the potential protective role of Apigenin, a natural flavonoid with demonstrated anti-inflammatory and antioxidant properties, against RT-induced esophageal injury in an experimental rat model. Material and Methods: A total of 40 rats were divided into four groups: RT, RT+Apigenin+Dimethyl sulfoxide (DMSO), RT+DMSO, and Apigenin+DMSO. A single 16 Gy dose of RT was given to the cervical area in the appropriate groups. Histopathological examination and tumor necrosis factor-alfa (TNF-α) expression analysis were used to evaluate tissue damage and inflammation. Results: Histopathological examination revealed marked hyperemia, microhemorrhages, erosions, and mild inflammatory response in the esophageal tissue of the RT group (p<0.001). In contrast, the RT+Apigenin+DMSO group exhibited a significant reduction in these histopathological findings (p<0.001). Immunohistochemical analysis revealed a significant increase in TNF-α expression in the esophageal epithelial cells of the RT group (p<0.001). In the RT+Apigenin+DMSO group, a marked decrease in TNF-α levels was observed (p<0.001). Conclusion: This study suggests that Apigenin may serve as a potential radioprotective agent against RT-induced esophageal toxicity, with histopathological and immunohistochemical findings supporting its protective effects. Further preclinical and controlled clinical studies are needed to confirm its translational applicability.

Keywords

• Apigenin
• Radiotherapy
• Esophagitis

References

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet‐Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108.
2. Global Burden of Disease Cancer Collaboration; Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505-27. Erratum in: JAMA Oncol. 2015;1(5):690.
3. Taslak Şengül A. Epidemiology of esophagus cancer. J Exp Clin Med. 2012;29(4S):S203-8. Turkish.
4. Werner-Wasik M, Paulus R, Curran WJ Jr, Byhardt R. Acute esophagitis and late lung toxicity in concurrent chemoradiotherapy trials in patients with locally advanced non-small-cell lung cancer: analysis of the Radiation Therapy Oncology Group (RTOG) database. Clin Lung Cancer. 2011;12(4):245-51.
5. Tanrıverdi Hİ, Şenel U, Markoç F. Corrosive effects of cleaning agents including hydrogen peroxide on esophagus at experimental rat model. Duzce Med J. 2014;16(3):5-8. Turkish.
6. Movsas B, Scott C, Langer C, Werner-Wasik M, Nicolaou N, Komaki R, et al. Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: Radiation Therapy Oncology Group trial 98-01. J Clin Oncol. 2005;23(10):2145-54.
7. Genvresse I, Lange C, Schanz J, Schweigert M, Harder H, Possinger K, et al. Tolerability of the cytoprotective agent amifostine in elderly patients receiving chemotherapy: a comparative study. Anticancer Drugs. 2001;12(4):345-9.
8. Allemailem KS, Almatroudi A, Alharbi HOA, AlSuhaymi N, Alsugoor MH, Aldakheel FM, et al. Apigenin: A bioflavonoid with a promising role in disease prevention and treatment. Biomedicines. 2024;12(6):1353.

9. Fossatelli L, Maroccia Z, Fiorentini C, Bonucci M. Resources for human health from the plant kingdom: the potential role of the flavonoid apigenin in cancer counteraction. Int J Mol Sci. 2023;25(1):251.
10. Woo ER, Pokharel YR, Yang JW, Lee SY, Kang KW. Inhibition of nuclear factor-kappaB activation by 2',8''-biapigenin. Biol Pharm Bull. 2006;29(5):976-80.
11. Rajabinasab F, Hajimirzaei P, Ramezani F, Moayer F, Gorjipour F, Nikoofar A, et al. Apigenin’s influence on inflammatory and epigenetic responses in rat lungs after radiotherapy. Curr Radiopharm. 2025;18(2):147-57.
12. Büyükçelik B, Tüz M, Özmen Ö, Kumbul YÇ, Sivrice ME, Yasan H, et al. Radioprotective effect of apigenin on the submandibular gland of irradiated rats. Turk J Ear Nose Throat. 2025;35(1):17-28.
13. Gradolatto A, Basly JP, Berges R, Teyssier C, Chagnon MC, Siess MH, et al. Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration. Drug Metab Dispos. 2005;33(1):49-54.
14. Krishnan M, Tennavan A, Saraswathy S, Sekhri T, Singh AK, Nair V. Acute radiation-induced changes in Sprague-Dawley rat submandibular glands: a histomorphometric analysis. World J Oncol. 2017;8(2):45-52.
15. Li Y, Lin J, Xiao J, Li Z, Chen JS, Wei L, et al. Therapeutic effects of Co-Venenum Bufonis oral liquid on radiation-induced esophagitis in rats. Exp Anim. 2020;69(3):354-62.
16. Broering DC, Walter J, Halata Z. Surgical anatomy of the esophagus. In: Izbicki JR, Broering DC, Yekebas EF, Kutup A, Chernousov AF, Gallinger YI, et al., editors. Surgery of the esophagus: Textbook and atlas of surgical practice. Germany: Steinkopff Verlag, Springer; 2009. p.3-10.
17. Güzle Adaş Y, Nalça Andrieu M. Esophagus cancer radiotherapy. Bulletin of Thoracic Surgery. 2013;4(1):53-7. Turkish.
18. Javle M, Ailawadhi S, Yang GY, Nwogu CE, Schiff MD, Nava HR. Palliation of malignant dysphagia in esophageal cancer: a literature-based review. J Support Oncol. 2006;4(8):365-73.
19. Karabulut Gül Ş, Oruç AF, Atalay R, Benli Yavuz B, Gedik D, Aksu A. The Effect of oral glutamine in the prevention of radiotherapy related esophagitis and weight loss in lung cancer patients. South Clin Ist Euras. 2016;27(1):37-41. Turkish.
20. Popović M, Caballero-Bleda M, Benavente-García O, Castillo J. The flavonoid apigenin delays forgetting of passive avoidance conditioning in rats. J Psychopharmacol. 2014;28(5):498-501.
21. Yan X, Qi M, Li P, Zhan Y, Shao H. Apigenin in cancer therapy: Anti-cancer effects and mechanisms of action. Cell Biosci. 2017;7:50.
22. Monadi T, Mohajer Z, Soltani A, Khazeei Tabari MA, Manayi A, Azadbakht M. The influence of apigenin on cellular responses to radiation: From protection to sensitization. Biofactors. 2025;51(1):e2113.
23. Patil RH, Babu RL, Naveen Kumar M, Kiran Kumar KM, Hegde SM, Nagesh R, et al. Anti-inflammatory effect of apigenin on LPS-induced pro-inflammatory mediators and AP-1 factors in human lung epithelial cells. Inflammation. 2016;39(1):138-47.
24. Tandon S, Gairola M, Pal M, Aggarwal A, Sharma K, Karimi AM, et al. The use of adaptive intensity-modulated radiotherapy in the treatment of small-cell carcinoma lung refractory to chemotherapy in a patient with preexisting interstitial lung disease. Lung India. 2018;35(1):54-7.
25. Zhang C, Zhang Y, Feng Z, Zhang F, Liu Z, Sun X, et al. Therapeutic effect of dental pulp stem cell transplantation on a rat model of radioactivity-induced esophageal injury. Cell Death Dis. 2018;9(7):738.
26. Dabak H, Karlidag T, Akpolat N, Keles E, Alpay HC, Serin M, et al. The effects of methylprednisolone and halofuginone on preventing esophageal and hypopharyngeal fibrosis in delivered radiotherapy. Eur Arch Otorhinolaryngol. 2010;267(9):1429-35.