Boric acid against tamoxifen resistance: an in vitro analysis of combined cytotoxic effects in MCF-7 breast cancer cells
Öz
Aim: Breast cancer is the most frequently diagnosed malignant neoplasm in women. Tamoxifen is widely used in patients with hormone receptor–positive tumors; however, one of the main challenges associated with its use is the development of resistance, which reduces treatment efficacy. This study aimed to evaluate the effect of boric acid on MCF-7 cells, a hormone receptor–positive human breast cancer cell line, and to investigate its potential modulatory effect when used in combination with tamoxifen.
Materials and Methods: In this study, MCF-7 cell lines were used. Tamoxifen and boric acid were applied to the cells at various doses and time points, both individually and in combination.
The effects on cell viability were assessed using the MTT assay. The half-maximal inhibitory concentrations (IC₅₀) for tamoxifen and boric acid were calculated at 24, 48, and 72 hours.
Results: Tamoxifen significantly reduced cell viability starting at 25 µM at 24 hours, 15 µM at 48 hours, and 5 µM at 72 hours (p < 0.05). The corresponding IC₅₀ values were 27,98 µM, 21,63 µM, and 18,22 µM at 24, 48, and 72 hours, respectively. Boric acid significantly reduced cell viability starting at 5 mM at 24 and 48 hours, and at 10 mM at 72 hours (p < 0.05). The IC₅₀ values for boric acid were calculated as 65,93 mM, 30,25 mM, and 25,40 mM at 24, 48, and 72 hours, respectively.
Conclusion: This study reveals the in vitro effects of boric acid on the MCF-7 cell line as a potential adjunct to tamoxifen therapy and provides a novel foundation for combination treatment strategies. In co-treatment experiments, tamoxifen and boric acid demonstrated an additive effect based on combination index analysis. However, further advanced experimental studies are needed to fully elucidate the underlying molecular mechanisms of this interaction.
Anahtar Kelimeler
Kaynakça
- Sancho-Garnier H, Colonna M. Breast cancer epidemiology. Presse Medicale (Paris, France: 1983). 2019;48(10):1076-84.
- Pusztai L, Mazouni C, Anderson K, Wu Y, Symmans WF. Molecular classification of breast cancer: limitations and potential. The oncologist. 2006;11(8):868-77.
- Parise CA, Bauer KR, Brown MM, Caggiano V. Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999–2004. The breast journal. 2009;15(6):593-602.
- Rodriguez D, Ramkairsingh M, Lin X, Kapoor A, Major P, Tang D. The central contributions of breast cancer stem cells in developing resistance to endocrine therapy in estrogen receptor (ER)-positive breast cancer. Cancers. 2019;11(7):1028.
- Johnston SR. Acquired tamoxifen resistance in human breast cancer–potential mechanisms and clinical implications. Anti-cancer drugs. 1997;8(10):911-30.
- Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. Journal of the National Cancer Institute. 2006;98(18):1285-91.
- National Cancer Institute. Tamoxifen [Internet]. Bethesda (MD): National Cancer Institute; 2021 [cited 2025 Apr 17]. Available from: https://evsexplore.semantics.cancer.gov/evsexplore/concept/ncit/ncit:C62078
- Yenmez N. Stratejik bir maden olarak bor minerallerin Türkiye için önemi. Coğrafya Dergisi. 2009(19):59-94.
- National Cancer Institute. Boric acid [Internet]. Bethesda (MD): National Cancer Institute; 2021 [cited 2025 Apr 17]. Available from: https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_
- 1PubChem. Boric acid [Internet]. Bethesda (MD): National Center for Biotechnology Information; 2021 [cited 2025 Apr 17]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Boric-Acid
- Groziak MP. Boron therapeutics on the horizon. American Journal of Therapeutics. 2001;8(5):321-8.
- Yang W, Gao X, Wang B. Boronic acid compounds as potential pharmaceutical agents. Medicinal Research Reviews. 2003;23(3):346-68.
- Jansen JA, Andersen J, Schou JS. Boric acid single dose pharmacokinetics after intravenous administration to man. Archives of toxicology. 1984;55:64-7.
- Schou J, Jansen J, Aggerbeck B, editors. Human pharmacokinetics and safety of boric acid. Disease, Metabolism and Reproduction in the Toxic Response to Drugs and Other Chemicals: Proceedings of the European Society of Toxicology Meeting Held in Rome, March 28–30, 1983; 1984: Springer.
- Linden CH, Hall AH, Kulig KW, Rumack BH. Acute ingestions of boric acid. Journal of Toxicology: Clinical Toxicology. 1986;24(4):269-79.
- Litovitz TL, Klein-Schwartz W, Oderda GM, Schmitz BF. Clinical manifestations of toxicity in a series of 784 boric acid ingestions. The American Journal of Emergency Medicine. 1988;6(3):209-13.
- Moseman RF. Chemical disposition of boron in animals and humans. Environmental health perspectives. 1994;102(suppl 7):113-7.
- Chou T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer research. 2010;70(2):440-6.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
- Rondón-Lagos M, Rangel N, Di Cantogno LV, Annaratone L, Castellano I, Russo R, et al. Effect of low doses of estradiol and tamoxifen on breast cancer cell karyotypes. Endocrine-Related Cancer. 2016;23(8):635.
- Zheng A, Kallio A, Harkonen P. Tamoxifen-induced rapid death of MCF-7 breast cancer cells is mediated via extracellularly signal-regulated kinase signaling and can be abrogated by estrogen. Endocrinology. 2007;148(6):2764-77.
- Bardon S, Vignon F, Derocq D, Rochefort H. The antiproliferative effect of tamoxifen in breast cancer cells: mediation by the estrogen receptor. Molecular and cellular endocrinology. 1984;35(2-3):89-96.
- Li W, Shi X, Xu Y, Wan J, Wei S, Zhu R. Tamoxifen promotes apoptosis and inhibits invasion in estrogen‑positive breast cancer MCF‑7 cells. Molecular medicine reports. 2017;16(1):478-84.
- Motawi TK, Abdelazim SA, Darwish HA, Elbaz EM, Shouman SA. Could caffeic acid phenethyl ester expand the antitumor effect of tamoxifen in breast carcinoma? Nutrition and Cancer. 2016;68(3):435-45.
- Hacioglu C, Kar F, Kacar S, Sahinturk V, Kanbak G. High concentrations of boric acid trigger concentration-dependent oxidative stress, apoptotic pathways and morphological alterations in DU-145 human prostate cancer cell line. Biological Trace Element Research. 2020;193:400-9.
- Çiğel A, Bilgin MD, Ek RO. Evaluation of the Anti-cancer and Biological Effects of Boric Acid on Colon Cancer Cell Line. Meandros Medical & Dental Journal. 2020;21(3).
- Scorei R, Ciubar R, Ciofrangeanu CM, Mitran V, Cimpean A, Iordachescu D. Comparative effects of boric acid and calcium fructoborate on breast cancer cells. Biological trace element research. 2008;122:197-205.
- Khazaei M, Pazhouhi M. Antiproliferative effect of Trifolium pratens L. extract in human breast cancer cells. Darakhshan S, Ghanbari A. Tamoxifen and tranilast show a synergistic effect against breast cancer in vitro. Bratislavske lekarske listy. 2015;116(1):69-73.
- Mannal P, McDonald D, McFadden D. Pterostilbene and tamoxifen show an additive effect against breast cancer in vitro. The American journal of surgery. 2010;200(5):577-80.
Tamoksifen direncine karşı borik asit: MCF-7 hücrelerinde kombine sitotoksik etkinin in vitro analizi
Öz
Amaç: Meme kanseri, kadınlarda en sık görülen malign neoplazidir. Hormon reseptörü pozitif hastalarda yaygın olarak kullanılan tamoksifenin etkinliği, zamanla gelişen direnç nedeniyle azalabilmektedir. Bu çalışmada, borik asidin hormon reseptörü pozitif insan meme kanseri hücre hattı olan MCF-7 üzerindeki etkisinin değerlendirilmesi ve tamoksifen ile birlikte kullanımının olası modülatör etkisinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: Çalışmada MCF-7 hücre dizileri kullanılmıştır. Tamoksifen ve borik asit, hücrelere farklı doz ve sürelerde ayrı ayrı ve kombine olarak uygulanmıştır. Hücre canlılığı üzerindeki etkiler MTT testi ile değerlendirilmiştir. Tamoksifen ve borik asit için, hücre canlılığını %50 oranında inhibe eden konsantrasyon (IC₅₀) değerleri 24., 48. ve 72. saatlerde hesaplanmıştır.
Bulgular: Tamoksifen, hücre canlılığını 24. saatte 25 µM, 48. saatte 15 µM ve 72. saatte 5 µM’den itibaren istatistiksel olarak anlamlı şekilde azaltmıştır (p<0,05). İlgili saatlerdeki IC₅₀ değerleri sırasıyla 27,98 µM, 21,63 µM ve 18,22 µM olarak bulunmuştur. Borik asit ise 24. ve 48. saatlerde 5 mM, 72. saatte ise 10 mM’den itibaren hücre canlılığını anlamlı olarak azaltmıştır (p<0,05); IC₅₀ değerleri sırasıyla 65,93 mM, 30,25 mM ve 25,40 mM olarak hesaplanmıştır.
Sonuç: Bu çalışma, tamoksifen tedavisini potansiyel olarak destekleyebilecek bir ajan olarak borik asidin MCF-7 hücre hattındaki in vitro etkilerini ortaya koymakta ve kombinasyon tedavilerine yönelik özgün bir temel sunmaktadır. Tamoksifen ve borik asidin birlikte uygulandığı deneylerde, kombinasyon indeksi analizlerine göre additif etki saptanmıştır. Ancak bu etkinin altında yatan moleküler mekanizmaların tam olarak aydınlatılabilmesi için ileri düzey deneysel çalışmalara ihtiyaç vardır.
Anahtar Kelimeler
Kaynakça
- Sancho-Garnier H, Colonna M. Breast cancer epidemiology. Presse Medicale (Paris, France: 1983). 2019;48(10):1076-84.
- Pusztai L, Mazouni C, Anderson K, Wu Y, Symmans WF. Molecular classification of breast cancer: limitations and potential. The oncologist. 2006;11(8):868-77.
- Parise CA, Bauer KR, Brown MM, Caggiano V. Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999–2004. The breast journal. 2009;15(6):593-602.
- Rodriguez D, Ramkairsingh M, Lin X, Kapoor A, Major P, Tang D. The central contributions of breast cancer stem cells in developing resistance to endocrine therapy in estrogen receptor (ER)-positive breast cancer. Cancers. 2019;11(7):1028.
- Johnston SR. Acquired tamoxifen resistance in human breast cancer–potential mechanisms and clinical implications. Anti-cancer drugs. 1997;8(10):911-30.
- Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. Journal of the National Cancer Institute. 2006;98(18):1285-91.
- National Cancer Institute. Tamoxifen [Internet]. Bethesda (MD): National Cancer Institute; 2021 [cited 2025 Apr 17]. Available from: https://evsexplore.semantics.cancer.gov/evsexplore/concept/ncit/ncit:C62078
- Yenmez N. Stratejik bir maden olarak bor minerallerin Türkiye için önemi. Coğrafya Dergisi. 2009(19):59-94.
- National Cancer Institute. Boric acid [Internet]. Bethesda (MD): National Cancer Institute; 2021 [cited 2025 Apr 17]. Available from: https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_
- 1PubChem. Boric acid [Internet]. Bethesda (MD): National Center for Biotechnology Information; 2021 [cited 2025 Apr 17]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Boric-Acid
- Groziak MP. Boron therapeutics on the horizon. American Journal of Therapeutics. 2001;8(5):321-8.
- Yang W, Gao X, Wang B. Boronic acid compounds as potential pharmaceutical agents. Medicinal Research Reviews. 2003;23(3):346-68.
- Jansen JA, Andersen J, Schou JS. Boric acid single dose pharmacokinetics after intravenous administration to man. Archives of toxicology. 1984;55:64-7.
- Schou J, Jansen J, Aggerbeck B, editors. Human pharmacokinetics and safety of boric acid. Disease, Metabolism and Reproduction in the Toxic Response to Drugs and Other Chemicals: Proceedings of the European Society of Toxicology Meeting Held in Rome, March 28–30, 1983; 1984: Springer.
- Linden CH, Hall AH, Kulig KW, Rumack BH. Acute ingestions of boric acid. Journal of Toxicology: Clinical Toxicology. 1986;24(4):269-79.
- Litovitz TL, Klein-Schwartz W, Oderda GM, Schmitz BF. Clinical manifestations of toxicity in a series of 784 boric acid ingestions. The American Journal of Emergency Medicine. 1988;6(3):209-13.
- Moseman RF. Chemical disposition of boron in animals and humans. Environmental health perspectives. 1994;102(suppl 7):113-7.
- Chou T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer research. 2010;70(2):440-6.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
- Rondón-Lagos M, Rangel N, Di Cantogno LV, Annaratone L, Castellano I, Russo R, et al. Effect of low doses of estradiol and tamoxifen on breast cancer cell karyotypes. Endocrine-Related Cancer. 2016;23(8):635.
- Zheng A, Kallio A, Harkonen P. Tamoxifen-induced rapid death of MCF-7 breast cancer cells is mediated via extracellularly signal-regulated kinase signaling and can be abrogated by estrogen. Endocrinology. 2007;148(6):2764-77.
- Bardon S, Vignon F, Derocq D, Rochefort H. The antiproliferative effect of tamoxifen in breast cancer cells: mediation by the estrogen receptor. Molecular and cellular endocrinology. 1984;35(2-3):89-96.
- Li W, Shi X, Xu Y, Wan J, Wei S, Zhu R. Tamoxifen promotes apoptosis and inhibits invasion in estrogen‑positive breast cancer MCF‑7 cells. Molecular medicine reports. 2017;16(1):478-84.
- Motawi TK, Abdelazim SA, Darwish HA, Elbaz EM, Shouman SA. Could caffeic acid phenethyl ester expand the antitumor effect of tamoxifen in breast carcinoma? Nutrition and Cancer. 2016;68(3):435-45.
- Hacioglu C, Kar F, Kacar S, Sahinturk V, Kanbak G. High concentrations of boric acid trigger concentration-dependent oxidative stress, apoptotic pathways and morphological alterations in DU-145 human prostate cancer cell line. Biological Trace Element Research. 2020;193:400-9.
- Çiğel A, Bilgin MD, Ek RO. Evaluation of the Anti-cancer and Biological Effects of Boric Acid on Colon Cancer Cell Line. Meandros Medical & Dental Journal. 2020;21(3).
- Scorei R, Ciubar R, Ciofrangeanu CM, Mitran V, Cimpean A, Iordachescu D. Comparative effects of boric acid and calcium fructoborate on breast cancer cells. Biological trace element research. 2008;122:197-205.
- Khazaei M, Pazhouhi M. Antiproliferative effect of Trifolium pratens L. extract in human breast cancer cells. Darakhshan S, Ghanbari A. Tamoxifen and tranilast show a synergistic effect against breast cancer in vitro. Bratislavske lekarske listy. 2015;116(1):69-73.
- Mannal P, McDonald D, McFadden D. Pterostilbene and tamoxifen show an additive effect against breast cancer in vitro. The American journal of surgery. 2010;200(5):577-80.
Ayrıntılar
| Birincil Dil | Türkçe |
|---|---|
| Konular | Klinik Onkoloji |
| Bölüm | Araştırma Makaleleri |
| Yazarlar | |
| Yayımlanma Tarihi | 8 Eylül 2025 |
| Gönderilme Tarihi | 17 Nisan 2025 |
| Kabul Tarihi | 16 Mayıs 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 64 Sayı: 3 |
