The Effects of Ferulic Acid on Proliferation and Apoptosis in Ishikawa Cells
Yıl 2026,
Cilt: 2 Sayı: 1, 10 - 18, 25.02.2026
Çiğdem Karaca
,
Esra Aslan
Öz
Purpose: This study investigated the impact of applying ferulic acid on cellular responses linked to cell proliferation and apoptosis in Ishikawa endometrial cancer cells.
Method: The effects of ferulic acid on the viability of Ishikawa cells were evaluated using an MTT assay. The application dose was determined based on preliminary experiments conducted over a wide dose range. Cellular morphological changes were examined using an inverted microscope. Cell proliferation was assessed using Ki-67 immunocytochemical staining, while the apoptotic response was analysed through Bax and Bcl-2 immunoreactivity and the Bax/Bcl-2 ratio.
Results: MTT analysis revealed that ferulic acid exhibited dose-dependent effects on cell viability, with a dose of 800 µM most effectively reducing viability to approximately 50%. Morphologically, ferulic acid -treated cells exhibited decreased cell density and disrupted monolayer integrity. Immunocytochemical analysis revealed decreased Ki-67 immunoreactivity and increased Bax and decreased Bcl-2 immunoreactivity, resulting in a significant increase in the Bax/Bcl-2 ratio.
Conclusion: These findings demonstrate that ferulic acid exhibits cytotoxic effects in Ishikawa endometrial cancer cells by suppressing proliferative activity and increasing apoptosis. These characteristics suggest that ferulic acid could be a candidate for supportive combination approaches to current endometrial cancer treatments. However, further experimental and clinical studies are required to evaluate this potential.
Etik Beyan
This study was conducted using an in vitro cell culture model only, with no human- or animal-derived tissue, cells or clinical data being used. Therefore, approval from an ethics committee was not required.
Teşekkür
We would like to thank MD Merve Bozkurt, for her contributions to the statistical analysis and evaluation of the findings in this study.
Kaynakça
-
1. Corr BR, Erickson BK, Barber EL, Fisher CM, Slomovitz B. Advances in the management of endometrial cancer. bmj. 2025;388.
-
2. Xu Y, Wang T, Liang X, Yang J, Zhang Y, Bao S. Global research trends and focus on immunotherapy for endometrial cancer: a comprehensive bibliometric insight and visualization analysis (2012-2024). Frontiers in Immunology. 2025;16:1571800.
-
3. Nishida M, Kasahara K, Kaneko M, Iwasaki H, Hayashi K. Establishment of a new human endometrial adenocarcinoma cell line, Ishikawa cells, containing estrogen and progesterone receptors. Nihon sanka fujinka gakkai zasshi. 1985;37(7):1103-11.
-
4. Pyrzynska K. Ferulic acid—a brief review of its extraction, bioavailability and biological activity. Separations. 2024;11(7):204.
-
5. Kumar N, Pruthi V. Potential applications of ferulic acid from natural sources. Biotechnology Reports. 2014;4:86-93.
-
6. Stompor-Gorący M, Machaczka M. Recent advances in biological activity, new formulations and prodrugs of ferulic acid. International journal of molecular sciences. 2021;22(23):12889.
-
7. Markowska A, Markowska J, Stanisławiak-Rudowicz J, Kozak K, Roubinek OK, Jasińska M. The Role of Ferulic Acid in Selected Malignant Neoplasms. Molecules. 2025;30(5):1018.
-
8. Wu X, Pan X, Kang J et al. Ferulic acid inhibits ox-LDL-induced ferroptosis and apoptosis in RAW 264.7 cells via the HIF-1 signaling pathway. Frontiers in Pharmacology. 2025;16:1524736.
-
9. Ahmmed S, Bhuia MS, Chowdhury R et al. Potential Therapeutic Efficacy of Ferulic Acid and Its Derivatives in the Management of Cancers: A Comprehensive Analysis With Mechanistic Insight. International Journal of Food Science. 2025;2025(1):2256871.
-
10. Rauf A, Ajaj R, Akram Z et al. Ferulic acid as a promising candidate for developing selective and effective anti-cancer therapies. Discover Oncology. 2025;16:1214.
-
11. Bao X, Li W, Jia R, Meng D, Zhang H, Xia L. Molecular mechanism of ferulic acid and its derivatives in tumor progression. Pharmacological Reports. 2023;75(4):891-906.
-
12. DiNicolantonio JJ, McCarty MF, Assanga SI, Lujan LL, O'Keefe JH. Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity. Open Heart. 2022;9(1).
-
13. Purushothaman JR, Rizwanullah M, Purushothaman Sr R. Ferulic acid: a comprehensive review. Cureus. 2024;16(8).
-
14. Andrés-Sánchez N, Fisher D, Krasinska L. Physiological functions and roles in cancer of the proliferation marker Ki-67. Journal of cell science. 2022;135(11):jcs258932.
-
15. Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J. The role of Bcl-2 family proteins in regulating apoptosis and cancer therapy. Frontiers in oncology. 2022;12:985363.
-
16. Helaly NA, Esheba NE, Abou Ammo DE, Elwan NM, Elkholy RA. High Bax/Bcl-2 ratio is associated with good prognosis and better survival in patients with B cell chronic lymphocytic leukemia. Leukemia Research. 2021;107:106604.
-
17. Mansour E, Abd-Rabou AA, El-Atawy MA, Ahmed HA, El-Farargy AF, Abd El-Mawgoud HK. Induction of breast cancer cell apoptosis by novel thiouracil-fused heterocyclic compounds through boosting of Bax/Bcl-2 ratio and DFT study. Bioorganic Chemistry. 2024;146:107292.
-
18. Nishida M. The Ishikawa cells from birth to the present. Human cell. 2002;15(3):104-17
-
19. Kanski J, Aksenova M, Stoyanova A, Butterfield DA. Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro: structure-activity studies. The Journal of nutritional biochemistry. 2002;13(5):273-81.
-
20. Janicke B, Hegardt C, Krogh M et al. The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells. Nutrition and cancer. 2011;63(4):611-22.
-
21. Afshari A, Moein M, Afsari A, Sabahi Z. Antiproliferative effects of ferulic, coumaric, and caffeic acids in HEPG2 cells by htert downregulation. Advances in Pharmacological and Pharmaceutical Sciences. 2022;2022(1):1850732.
-
22. Wang J, Lai X, Yuan D, Liu Y, Wang J, Liang Y. Effects of ferulic acid, a major component of rice bran, on proliferation, apoptosis, and autophagy of HepG2 cells. Food Research International. 2022;161:111816.
-
23. Dai X-s, Wei Q-h, Guo X et al. Ferulic acid, ligustrazine, and tetrahydropalmatine display the anti-proliferative effect in endometriosis through regulating Notch pathway. Life Sciences. 2023;328:121921.
-
24. Chen S, Zhao D, Luan C et al. Ferulic acid induces autophagy and apoptosis in colon cancer CT26 cells via the MAPK pathway. Molecules. 2023;28(16):6014.
-
25. Bouzaiene NN, Jaziri SK, Kovacic H, Chekir-Ghedira L, Ghedira K, Luis J. The effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro. European Journal of Pharmacology. 2015;766:99-105.
-
26. Gadelmawla MH, Alazzouni AS, Farag AH, Gabri MS, Hassan BN. Enhanced effects of ferulic acid against the harmful side effects of chemotherapy in colon cancer: docking and in vivo study. The Journal of Basic and Applied Zoology. 2022;83(1):28.
-
27. Wang T, Gong X, Jiang R, Li H, Du W, Kuang G. Ferulic acid inhibits proliferation and promotes apoptosis via blockage of PI3K/Akt pathway in osteosarcoma cell. American journal of translational research. 2016;8(2):968.
-
28. Eroğlu C, Seçme M, Bağcı G, Dodurga Y. Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines. Tumor Biology. 2015;36(12):9437-46.
-
29. Naseri KM, Kalantar H, Khodayar MJ. Cytotoxic and apoptotic effects of ferulic acid on renal carcinoma cell line (ACHN). 2020.
-
30. Luo L, Zhu S, Tong Y, Peng S. Ferulic acid induces apoptosis of HeLa and Caski cervical carcinoma cells by down-regulating the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2020;26:e920095-1.
FERULİK ASİDİN ISHIKAWA HÜCRELERİNDE ÇOĞALMA VE APOPTOSİS ÜZERİNDEKİ ETKİLERİ
Yıl 2026,
Cilt: 2 Sayı: 1, 10 - 18, 25.02.2026
Çiğdem Karaca
,
Esra Aslan
Öz
Amaç: Bu çalışmada, ferulik asit uygulamasının Ishikawa endometriyal kanser hücrelerinde hücre proliferasyonu ve apoptoz ile ilişkili hücresel yanıtlar üzerindeki etkilerinin araştırılması hedeflenmiştir. Yöntem: Ishikawa hücrelerinde ferulik asitin hücre canlılığı üzerindeki etkileri MTT analizi ile değerlendirilmiş ve geniş bir doz aralığında yapılan ön deneyler sonucunda uygulama dozu belirlenmiştir. Hücresel morfolojik değişiklikler invert mikroskop ile incelenmiştir. Hücre proliferasyonu Ki-67 immünositokimyasal boyaması ile değerlendirilirken, apoptotik yanıt Bax ve Bcl-2 immünoreaktiviteleri ile Bax/Bcl-2 oranı üzerinden analiz edilmiştir. Bulgular: MTT analizi sonucunda ferulik asitin hücre canlılığı üzerinde doz-bağımlı etkiler gösterdiği ve hücre canlılığını %50 düzeyine en yakın şekilde düşüren dozun 800 µM olduğu belirlenmiştir. Ferulik asit uygulanan hücrelerde morfolojik olarak hücre yoğunluğunda azalma ve monolayer bütünlüğünde bozulma gözlenirken, immünositokimyasal analizde Ki-67 immünoreaktivitesinde azalma, Bax immünoreaktivitesinde artış, Bcl-2 immünoreaktivitesinde azalma ve Bax/Bcl-2 oranında da belirgin artma olduğu tespit edilmiştir. Sonuç: Bu bulgular, ferulik asitin Ishikawa endometriyal kanser hücrelerinde sitotoksik etki göstererek proliferatif aktiviteyi baskıladığını ve apoptozisi artırdığını ortaya koymaktadır. ferulik asitin bu özellikleri, endometrium kanserinde mevcut tedavilere destekleyici kombinasyon yaklaşımlarında potansiyel bir aday olabileceğini düşündürmektedir. Bununla birlikte, bu potansiyelin klinik açıdan değerlendirilmesi ileri deneysel ve klinik çalışmalarla desteklenmelidir.
Etik Beyan
Bu çalışma yalnızca in vitro hücre kültürü modeli kullanılarak gerçekleştirilmiş olup, insan veya hayvan kaynaklı doku, hücre veya klinik veriler kullanılmamıştır. Bu nedenle, etik kurul onayı gerekmemiştir.
Teşekkür
Bu çalışmanın istatistiksel analizine ve bulgularının değerlendirilmesine katkılarından dolayı Uzm. Dr. Merve Bozkurt'a teşekkür ederiz.
Kaynakça
-
1. Corr BR, Erickson BK, Barber EL, Fisher CM, Slomovitz B. Advances in the management of endometrial cancer. bmj. 2025;388.
-
2. Xu Y, Wang T, Liang X, Yang J, Zhang Y, Bao S. Global research trends and focus on immunotherapy for endometrial cancer: a comprehensive bibliometric insight and visualization analysis (2012-2024). Frontiers in Immunology. 2025;16:1571800.
-
3. Nishida M, Kasahara K, Kaneko M, Iwasaki H, Hayashi K. Establishment of a new human endometrial adenocarcinoma cell line, Ishikawa cells, containing estrogen and progesterone receptors. Nihon sanka fujinka gakkai zasshi. 1985;37(7):1103-11.
-
4. Pyrzynska K. Ferulic acid—a brief review of its extraction, bioavailability and biological activity. Separations. 2024;11(7):204.
-
5. Kumar N, Pruthi V. Potential applications of ferulic acid from natural sources. Biotechnology Reports. 2014;4:86-93.
-
6. Stompor-Gorący M, Machaczka M. Recent advances in biological activity, new formulations and prodrugs of ferulic acid. International journal of molecular sciences. 2021;22(23):12889.
-
7. Markowska A, Markowska J, Stanisławiak-Rudowicz J, Kozak K, Roubinek OK, Jasińska M. The Role of Ferulic Acid in Selected Malignant Neoplasms. Molecules. 2025;30(5):1018.
-
8. Wu X, Pan X, Kang J et al. Ferulic acid inhibits ox-LDL-induced ferroptosis and apoptosis in RAW 264.7 cells via the HIF-1 signaling pathway. Frontiers in Pharmacology. 2025;16:1524736.
-
9. Ahmmed S, Bhuia MS, Chowdhury R et al. Potential Therapeutic Efficacy of Ferulic Acid and Its Derivatives in the Management of Cancers: A Comprehensive Analysis With Mechanistic Insight. International Journal of Food Science. 2025;2025(1):2256871.
-
10. Rauf A, Ajaj R, Akram Z et al. Ferulic acid as a promising candidate for developing selective and effective anti-cancer therapies. Discover Oncology. 2025;16:1214.
-
11. Bao X, Li W, Jia R, Meng D, Zhang H, Xia L. Molecular mechanism of ferulic acid and its derivatives in tumor progression. Pharmacological Reports. 2023;75(4):891-906.
-
12. DiNicolantonio JJ, McCarty MF, Assanga SI, Lujan LL, O'Keefe JH. Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity. Open Heart. 2022;9(1).
-
13. Purushothaman JR, Rizwanullah M, Purushothaman Sr R. Ferulic acid: a comprehensive review. Cureus. 2024;16(8).
-
14. Andrés-Sánchez N, Fisher D, Krasinska L. Physiological functions and roles in cancer of the proliferation marker Ki-67. Journal of cell science. 2022;135(11):jcs258932.
-
15. Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J. The role of Bcl-2 family proteins in regulating apoptosis and cancer therapy. Frontiers in oncology. 2022;12:985363.
-
16. Helaly NA, Esheba NE, Abou Ammo DE, Elwan NM, Elkholy RA. High Bax/Bcl-2 ratio is associated with good prognosis and better survival in patients with B cell chronic lymphocytic leukemia. Leukemia Research. 2021;107:106604.
-
17. Mansour E, Abd-Rabou AA, El-Atawy MA, Ahmed HA, El-Farargy AF, Abd El-Mawgoud HK. Induction of breast cancer cell apoptosis by novel thiouracil-fused heterocyclic compounds through boosting of Bax/Bcl-2 ratio and DFT study. Bioorganic Chemistry. 2024;146:107292.
-
18. Nishida M. The Ishikawa cells from birth to the present. Human cell. 2002;15(3):104-17
-
19. Kanski J, Aksenova M, Stoyanova A, Butterfield DA. Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro: structure-activity studies. The Journal of nutritional biochemistry. 2002;13(5):273-81.
-
20. Janicke B, Hegardt C, Krogh M et al. The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells. Nutrition and cancer. 2011;63(4):611-22.
-
21. Afshari A, Moein M, Afsari A, Sabahi Z. Antiproliferative effects of ferulic, coumaric, and caffeic acids in HEPG2 cells by htert downregulation. Advances in Pharmacological and Pharmaceutical Sciences. 2022;2022(1):1850732.
-
22. Wang J, Lai X, Yuan D, Liu Y, Wang J, Liang Y. Effects of ferulic acid, a major component of rice bran, on proliferation, apoptosis, and autophagy of HepG2 cells. Food Research International. 2022;161:111816.
-
23. Dai X-s, Wei Q-h, Guo X et al. Ferulic acid, ligustrazine, and tetrahydropalmatine display the anti-proliferative effect in endometriosis through regulating Notch pathway. Life Sciences. 2023;328:121921.
-
24. Chen S, Zhao D, Luan C et al. Ferulic acid induces autophagy and apoptosis in colon cancer CT26 cells via the MAPK pathway. Molecules. 2023;28(16):6014.
-
25. Bouzaiene NN, Jaziri SK, Kovacic H, Chekir-Ghedira L, Ghedira K, Luis J. The effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro. European Journal of Pharmacology. 2015;766:99-105.
-
26. Gadelmawla MH, Alazzouni AS, Farag AH, Gabri MS, Hassan BN. Enhanced effects of ferulic acid against the harmful side effects of chemotherapy in colon cancer: docking and in vivo study. The Journal of Basic and Applied Zoology. 2022;83(1):28.
-
27. Wang T, Gong X, Jiang R, Li H, Du W, Kuang G. Ferulic acid inhibits proliferation and promotes apoptosis via blockage of PI3K/Akt pathway in osteosarcoma cell. American journal of translational research. 2016;8(2):968.
-
28. Eroğlu C, Seçme M, Bağcı G, Dodurga Y. Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines. Tumor Biology. 2015;36(12):9437-46.
-
29. Naseri KM, Kalantar H, Khodayar MJ. Cytotoxic and apoptotic effects of ferulic acid on renal carcinoma cell line (ACHN). 2020.
-
30. Luo L, Zhu S, Tong Y, Peng S. Ferulic acid induces apoptosis of HeLa and Caski cervical carcinoma cells by down-regulating the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2020;26:e920095-1.