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Boraks Endometriyal Adenokarsinomu Ishikawa Hücrelerinde Ferroptoz Sinyal Yolağını İndükleyerek Hücresel Canlılığı Baskılar

Year 2025, Volume: 11 Issue: 3, 477 - 484, 29.09.2025
https://doi.org/10.53394/akd.1657577

Abstract

Amaç: Endometrial kanser, dünya çapında kadınlarda en sık teşhis edilen dördüncü malignite ve kanserle ilişkili ölümlerin sekizinci önde gelen nedenidir. Yeni tanımlanan bir düzenlenmiş hücre ölümü biçimi olan ferroptozis, çeşitli yollar aracılığıyla lipid peroksidasyonunu düzenlemede önemli bir rol oynar ve kanserogenezin hem ilerlemesi hem de tedavi stratejileriyle yakından ilişkilidir. Bu çalışma, boraksla tedavi edilen Ishikawa hücrelerinde ferroptozis yollarının indüklenmesini araştırmayı amaçlamıştır.
Gereç ve Yöntemler: Boraksın etkilerini değerlendirmek için, Ishikawa hücrelerinde hücre canlılığı ve çoğalması değerlendirmeleri yapılmıştır. Boraksın sitotoksik konsantrasyonlarının belirlenmesinin ardından, Fe²⁺, malondialdehit (MDA), glutatyon (GSH), glutatyon peroksidaz 4 (GPx4) ve asil-CoA sentetaz uzun zincirli aile üyesi 4 (ACSL4) düzeylerinin kantifikasyonuyla birlikte morfolojik analizler gerçekleştirilmiştir.
Bulgular: Sonuçlar boraksın Ishikawa hücre canlılığını konsantrasyon ve zamana bağlı bir şekilde azalttığını ortaya koydu. Ayrıca boraks, Ishikawa hücrelerinde hücre çoğalmasını önemli ölçüde engelledi. Ters mikroskopik görüntüleme, boraksın nükleer anormallikleri indüklediğini ve genel hücre sayısını azalttığını gösterdi. Sonuçlar ayrıca boraks tedavisinin GSH ve GPx4 seviyelerinde azalmaya yol açarken Fe²⁺, MDA ve ACSL4 seviyelerini artırdığını gösterdi.
Sonuç: Bu bulgular boraksın ferroptoz sinyal yolunu düzenleyerek Ishikawa hücreleri için potansiyel bir antikanser ajanı olarak hizmet edebileceğini düşündürmektedir.

References

  • 1. Brüggmann D, Ouassou K, Klingelhöfer D, Bohlmann MK, Jaque J, Groneberg DA. Endometrial cancer: mapping the global landscape of research. J Transl Med 2020; 18(1):386.
  • 2. Tülüce Y, Lak PTA, Koyuncu İ, Kılıç A, Durgun M, Özkol H. The apoptotic, cytotoxic and genotoxic effect of novel binuclear boron-fluoride complex on endometrial cancer. Biometals 2017; 30(6):933-44.
  • 3. Humber CE, Tierney JF, Symonds RP, Collingwood M, Kirwan J, Williams C, Green JA. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol 2007; 18(3):409-420.
  • 4. Lortet-Tieulent J, Ferlay J, Bray F, Jemal A. International Patterns and Trends in Endometrial Cancer Incidence, 1978-2013. J Natl Cancer Inst 2018; 110(4):354-61.
  • 5. Bell DW, Ellenson LH. Molecular Genetics of Endometrial Carcinoma. Annu Rev Pathol 2019; 14:339-67.
  • 6. Kuru R, Yilmaz S, Tasli PN, Yarat A, Sahin F. Boron Content of Some Foods Consumed in Istanbul, Turkey. Biol Trace Elem Res 2019; 187(1):1-8.
  • 7. Bradke TM, Hall C, Carper SW, Plopper GE. Phenylboronic acid selectively inhibits human prostate and breast cancer cell migration and decreases viability. Cell Adh Migr 2008; 2(3):153-160.
  • 8. Rainey CJ, Nyquist LA, Christensen RE, Strong PL, Culver BD, Coughlin JR. Daily boron intake from the American diet. J Am Diet Assoc 1999; 99(3):335-40.
  • 9. Nielsen FH. Update on human health effects of boron. J Trace Elem Med Biol 2014; 28(4):383-7.
  • 10. Cui Y, Winton MI, Zhang ZF, Rainey C, Marshall J, De Kernion JB, Eckhert CD. Dietary boron intake and prostate cancer risk. Oncol Rep 2004; 11(4):887-92.
  • 11. Mahabir S, Spitz MR, Barrera SL, Dong YQ, Eastham C, Forman MR. Dietary boron and hormone replacement therapy as risk factors for lung cancer in women. Am J Epidemiol 2008; 167(9):1070-1080.
  • 12. Barranco WT, Eckhert CD. Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett 2004; 216(1):21-9.
  • 13. Acerbo AS, Miller LM. Assessment of the chemical changes induced in human melanoma cells by boric acid treatment using infrared imaging. Analyst 2009; 134(8):1669-74.
  • 14. Tuncer C, Hacioglu C. Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways. J Cell Mol Med 2024; 28(7):e18206.
  • 15. Hacioglu C, Oral D. Borax affects cellular viability by inducing ER stress in hepatocellular carcinoma cells by targeting SLC12A5. J Cell Mol Med 2024; 28(10):e18380.
  • 16. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072.
  • 17. Ng SW, Norwitz SG, Taylor HS, Norwitz ER. Endometriosis: The Role of Iron Overload and Ferroptosis. Reprod Sci 2020; 27(7):1383-90.
  • 18. Çil N, Önder E, Damar AN, Tabatabaei S, Çabuş Ü, Mete GA. In vitro cytotoxic and apoptotic effects of boric acid on endometrial adenocarcinoma cell lines (HEC-1B and Ischikawa). Med Oncol 2025; 42(3):79.
  • 19. Sevimli M, Bayram D, Özgöçmen M, Armağan I, Semerci Sevimli T. Boric acid suppresses cell proliferation by TNF signaling pathway mediated apoptosis in SW-480 human colon cancer line. J Trace Elem Med Biol 2022; 71:126958.
  • 20. Canturk Z, Tunali Y, Korkmaz S, Gulbaş Z. Cytotoxic and apoptotic effects of boron compounds on leukemia cell line. Cytotechnology 2016; 68(1):87-93.
  • 21. Barranco WT, Eckhert CD. Cellular changes in boric acid-treated DU-145 prostate cancer cells. Br J Cancer 2006; 94(6):884-890.
  • 22. Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Autophagy 2021; 17(9):2054-81.
  • 23. Bielfeld AP, Pour SJ, Poschmann G, Stühler K, Krüssel JS, Baston-Büst DM. A Proteome Approach Reveals Differences between Fertile Women and Patients with Repeated Implantation Failure on Endometrial Level⁻Does hCG Render the Endometrium of RIF Patients?. Int J Mol Sci 2019; 20(2):425.
  • 24. Zhang M, Zhang T, Song C, Qu J, Gu Y, Liu S, Li H, Xiao W, Kong L, Sun Y, Lv W. Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis. J Ethnopharmacol 2021; 274:114064.
  • 25. Wang H, Peng S, Cai J, Bao S. Silencing of PTPN18 Induced Ferroptosis in Endometrial Cancer Cells Through p-P38-Mediated GPX4/xCT Down-Regulation. Cancer Manag Res 2021; 13:1757-65.
  • 26. Zhang Y, Xia M, Zhou Z, Hu X, Wang J, Zhang M, Li Y, Sun L, Chen F, Yu H. p53 Promoted Ferroptosis in Ovarian Cancer Cells Treated with Human Serum Incubated-Superparamagnetic Iron Oxides. Int J Nanomedicine 2021; 16:283-296.

Borax Suppresses Cellular Viability by Inducing Ferroptosis Signaling Pathway in Endometrial Adenocarcinoma Ishikawa Cells

Year 2025, Volume: 11 Issue: 3, 477 - 484, 29.09.2025
https://doi.org/10.53394/akd.1657577

Abstract

Objective: Endometrial cancer is the fourth most frequently diagnosed malignancy and the eighth leading cause of cancer-related mortality among females worldwide. Ferroptosis, a newly identified form of regulated cell death, plays a crucial role in modulating lipid peroxidation through various pathways and is closely associated with both the progression and therapeutic strategies of cancerogenesis. This study aimed to investigate the induction of ferroptosis pathways in borax-treated Ishikawa cells.
Material and Methods: To evaluate the effects of borax, assessments of cell viability and proliferation were conducted on Ishikawa cells. Following the determination of borax's cytotoxic concentrations, morphological analyses were performed alongside the quantification of Fe²⁺, malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase 4 (GPx4), and acyl-CoA synthetase long-chain family member 4 (ACSL4) levels.
Results: The findings revealed that borax reduced Ishikawa cell viability in a concentration- and time-dependent manner. Furthermore, borax significantly inhibited cell proliferation in Ishikawa cells. Inverted microscopic imaging demonstrated that borax induced nuclear abnormalities and reduced the overall cell count. The results further indicated that borax treatment led to a decrease in GSH and GPx4 levels while increasing Fe²⁺, MDA, and ACSL4 levels.
Conclusion: These findings suggest that borax may serve as a potential anticancer agent for Ishikawa cells by modulating the ferroptosis signaling pathway.

References

  • 1. Brüggmann D, Ouassou K, Klingelhöfer D, Bohlmann MK, Jaque J, Groneberg DA. Endometrial cancer: mapping the global landscape of research. J Transl Med 2020; 18(1):386.
  • 2. Tülüce Y, Lak PTA, Koyuncu İ, Kılıç A, Durgun M, Özkol H. The apoptotic, cytotoxic and genotoxic effect of novel binuclear boron-fluoride complex on endometrial cancer. Biometals 2017; 30(6):933-44.
  • 3. Humber CE, Tierney JF, Symonds RP, Collingwood M, Kirwan J, Williams C, Green JA. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol 2007; 18(3):409-420.
  • 4. Lortet-Tieulent J, Ferlay J, Bray F, Jemal A. International Patterns and Trends in Endometrial Cancer Incidence, 1978-2013. J Natl Cancer Inst 2018; 110(4):354-61.
  • 5. Bell DW, Ellenson LH. Molecular Genetics of Endometrial Carcinoma. Annu Rev Pathol 2019; 14:339-67.
  • 6. Kuru R, Yilmaz S, Tasli PN, Yarat A, Sahin F. Boron Content of Some Foods Consumed in Istanbul, Turkey. Biol Trace Elem Res 2019; 187(1):1-8.
  • 7. Bradke TM, Hall C, Carper SW, Plopper GE. Phenylboronic acid selectively inhibits human prostate and breast cancer cell migration and decreases viability. Cell Adh Migr 2008; 2(3):153-160.
  • 8. Rainey CJ, Nyquist LA, Christensen RE, Strong PL, Culver BD, Coughlin JR. Daily boron intake from the American diet. J Am Diet Assoc 1999; 99(3):335-40.
  • 9. Nielsen FH. Update on human health effects of boron. J Trace Elem Med Biol 2014; 28(4):383-7.
  • 10. Cui Y, Winton MI, Zhang ZF, Rainey C, Marshall J, De Kernion JB, Eckhert CD. Dietary boron intake and prostate cancer risk. Oncol Rep 2004; 11(4):887-92.
  • 11. Mahabir S, Spitz MR, Barrera SL, Dong YQ, Eastham C, Forman MR. Dietary boron and hormone replacement therapy as risk factors for lung cancer in women. Am J Epidemiol 2008; 167(9):1070-1080.
  • 12. Barranco WT, Eckhert CD. Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett 2004; 216(1):21-9.
  • 13. Acerbo AS, Miller LM. Assessment of the chemical changes induced in human melanoma cells by boric acid treatment using infrared imaging. Analyst 2009; 134(8):1669-74.
  • 14. Tuncer C, Hacioglu C. Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways. J Cell Mol Med 2024; 28(7):e18206.
  • 15. Hacioglu C, Oral D. Borax affects cellular viability by inducing ER stress in hepatocellular carcinoma cells by targeting SLC12A5. J Cell Mol Med 2024; 28(10):e18380.
  • 16. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072.
  • 17. Ng SW, Norwitz SG, Taylor HS, Norwitz ER. Endometriosis: The Role of Iron Overload and Ferroptosis. Reprod Sci 2020; 27(7):1383-90.
  • 18. Çil N, Önder E, Damar AN, Tabatabaei S, Çabuş Ü, Mete GA. In vitro cytotoxic and apoptotic effects of boric acid on endometrial adenocarcinoma cell lines (HEC-1B and Ischikawa). Med Oncol 2025; 42(3):79.
  • 19. Sevimli M, Bayram D, Özgöçmen M, Armağan I, Semerci Sevimli T. Boric acid suppresses cell proliferation by TNF signaling pathway mediated apoptosis in SW-480 human colon cancer line. J Trace Elem Med Biol 2022; 71:126958.
  • 20. Canturk Z, Tunali Y, Korkmaz S, Gulbaş Z. Cytotoxic and apoptotic effects of boron compounds on leukemia cell line. Cytotechnology 2016; 68(1):87-93.
  • 21. Barranco WT, Eckhert CD. Cellular changes in boric acid-treated DU-145 prostate cancer cells. Br J Cancer 2006; 94(6):884-890.
  • 22. Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Autophagy 2021; 17(9):2054-81.
  • 23. Bielfeld AP, Pour SJ, Poschmann G, Stühler K, Krüssel JS, Baston-Büst DM. A Proteome Approach Reveals Differences between Fertile Women and Patients with Repeated Implantation Failure on Endometrial Level⁻Does hCG Render the Endometrium of RIF Patients?. Int J Mol Sci 2019; 20(2):425.
  • 24. Zhang M, Zhang T, Song C, Qu J, Gu Y, Liu S, Li H, Xiao W, Kong L, Sun Y, Lv W. Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis. J Ethnopharmacol 2021; 274:114064.
  • 25. Wang H, Peng S, Cai J, Bao S. Silencing of PTPN18 Induced Ferroptosis in Endometrial Cancer Cells Through p-P38-Mediated GPX4/xCT Down-Regulation. Cancer Manag Res 2021; 13:1757-65.
  • 26. Zhang Y, Xia M, Zhou Z, Hu X, Wang J, Zhang M, Li Y, Sun L, Chen F, Yu H. p53 Promoted Ferroptosis in Ovarian Cancer Cells Treated with Human Serum Incubated-Superparamagnetic Iron Oxides. Int J Nanomedicine 2021; 16:283-296.
There are 26 citations in total.

Details

Primary Language Turkish
Subjects Obstetrics and Gynaecology
Journal Section Research Article
Authors

Betül Keyif 0000-0002-7472-551X

Ceyhan Hacıoğlu 0000-0002-0993-6118

Early Pub Date September 22, 2025
Publication Date September 29, 2025
Submission Date March 14, 2025
Acceptance Date May 4, 2025
Published in Issue Year 2025 Volume: 11 Issue: 3

Cite

Vancouver Keyif B, Hacıoğlu C. Boraks Endometriyal Adenokarsinomu Ishikawa Hücrelerinde Ferroptoz Sinyal Yolağını İndükleyerek Hücresel Canlılığı Baskılar. Akd Med J. 2025;11(3):477-84.