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Kolorektal Kanser Hücrelerinde Boraksın Gpx4/ACSL4 Sinyal Yolu Aracılığıyla Sitotoksik Etkileri

Yıl 2023, Cilt: 13 Sayı: 1, 54 - 60, 20.01.2023
https://doi.org/10.33631/sabd.1180766

Öz

Amaç: Kolorektal kanser (CRC), kansere bağlı ölümlerin yaklaşık %10'unu oluşturmasıyla, malignite yönünden üçüncü ve kansere bağlı ölümlerde ikinci sırada yer almaktadır. Ferroptoz, CRC dahil çok sayıda kanserin tedavisinde ilaç direncini önlemede terapötiklerin anti-kanser etkinliğini arttırabilecek potansiyel demire bağlı hücre ölüm yolağıdır. Bu çalışmada CRC hücrelerinde ferroptozu sinyal yolağı üzerinden boraksın anti-proliferatif etkilerini araştırmak amaçlandı.
Gereç ve Yöntemler: Öncelikle, boraksın sitotoksik konsantrasyonları (0-64 mM aralığında) 3-(4,5-dimetiltiazol-2-il)-2,5-difenil tetrazolyum bromür (MTT) testi ile belirlendi. Daha sonra sitotoksik boraks konsantrasyonları ile 24 saat inkübe edilen HCT-116 hücrelerinde glutatyon peroksidaz 4 (GPx4), açil-KoA sentetaz uzun zincirli aile üyesi 4 (ACSL4), malondialdehit (MDA) ve 8-hidroksideoksiguanozin (8-OHdG) seviyeleri belirlendi.
Bulgular: 1 ve 4 mM boraks konsantrasyonları hücre canlılığını etkilemezken, 8 mM ve üzerindeki boraks konsantrasyonları HTC-116 hücrelerinde canlılığı anlamlı şekilde düşürmüştür (p<0,05). MTT sonuçlarına göre, boraksın IC25 ve IC50 konsantrasyonları sırasıyla 12,5 mM ve 20,8 mM olarak belirlendi. HTC-116 hücrelerinde 24 saat boyunca 12.5, 16,2 ve 20,8 mM boraks maruziyeti GPx4 seviyelerinde konsantrasyon bağlım şekilde düşüş olurken, ACSL4 seviyelerinde artış olmuştur. Ayrıca, HTC-116 hücrelerine artan boraks uygulamasının, kontrole kıyasla MDA ve 8-OHdG seviyelerinde önemli bir artış ile lipit peroksidasyonuna ve DNA hasarına neden olduğu bulundu (p<0,05).
Sonuç: Deneysel verilerimiz doğrultusunda, boraks insan CRC hücrelerinde potansiyel bir anti-kanser ajanı olarak ferroptozu indükleyerek anti-proliferatif etkiler göstermiştir.

Kaynakça

  • Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019; 394(10207): 1467-80.
  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394-424.
  • Henrikson NB, Webber EM, Goddard KA, Scrol A, Piper M, Williams MS, et al. Family history and the natural history of colorectal cancer: systematic review. Genet Med. 2015; 17(9): 702-12.
  • Schoen RE, Razzak A, Yu KJ, Berndt SI, Firl K, Riley TL, et al. Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer. Gastroenterology. 2015; 149(6): 1438-45.
  • Mishra J, Drummond J, Quazi SH, Karanki SS, Shaw JJ, Chen B, et al. Prospective of colon cancer treatments and scope for combinatorial approach to enhanced cancer cell apoptosis. Crit Rev Oncol Hematol. 2013; 86(3): 232-50.
  • DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014; 64(4): 252-71.
  • Dixon SJ. Ferroptosis: bug or feature? Immunol Rev. 2017; 277: 150-7.
  • Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016; 73: 2195-209.
  • Bano I, Horky P, Abbas SQ, Majid M, Bilal AHM, Ali F, et al. Ferroptosis: A new road towards cancer management. Molecules. 2022; 27(7): 2129.
  • Guo C, Liu P, Deng G, Han Y, Chen Y, Cai C, et al. Honokiol induces ferroptosis in colon cancer cells by regulating GPX4 activity. Am J Cancer Res. 2021; 11(6): 3039-54.
  • Yılmaz S, Ustundag A, Cemiloglu Ulker O, Duydu Y. Protective effect of boric acid on oxidative DNA damage in chinese hamster lung fibroblast V79 cell lines. Cell J. 2016; 17(4): 748-54.
  • Turkez H, Geyikoglu F, Tatar A, Keles MS, Kaplan I. The effects of some boron compounds against heavy metal toxicity in human blood. Exp Toxicol Pathol. 2012; 64(1-2): 93-101.
  • Kar F, Hacioglu C, Senturk H, Donmez DB, Kanbak G. The role of oxidative stress, renal inflammation, and apoptosis in post ischemic reperfusion ınjury of kidney tissue: the protective effect of dose-dependent boric acid administration. Biol Trace Elem Res. 2020; 195(1): 150-8.
  • Özyarım ŞC, Karabağ Çoban F. Investigation of the apoptotic and antiproliferative effects of boron on CCL-233 human colon cancer cells. Cell J. 2021; 23(4): 429-34.
  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1): 265-75.
  • Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer ıncidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol. 2017; 3(4): 524-48.
  • Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet. 2010; 375(9719): 1030-47.
  • Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: A Review. JAMA. 2021; 325(7): 669-85.
  • Rajamanickam S, Agarwal R. Natural products and colon cancer: current status and future prospects. Drug Dev Res. 2008; 69(7): 460-71.
  • Hadrup N, Frederiksen M, Sharma AK. Toxicity of boric acid, borax and other boron containing compounds: A review. Regul Toxicol Pharmacol. 2021; 121: 104873.
  • Yang W, Gao X, Wang B. Boronic acid compounds as potential pharmaceutical agents. Med Res Rev. 2003; 23(3): 346-68.
  • Deshayes S, Cabral H, Ishii T, Miura Y, Kobayashi S, Yamashita T, et al. Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J Am Chem Soc. 2013; 135(41): 15501-7.
  • 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.
  • Wade TB, Eckhert CD. Boric acid inhibits human prostate can- cer cell proliferation. Cancer Lett. 2004; 216(1): 21-9.
  • 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.
  • 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. Biol Trace Elem Res. 2020; 193(2): 400-9.
  • 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.
  • 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): 153-60.
  • Scorei R, Ciubar R, Ciofrangeanu CM, Mitran V, Cimpean A, Iordachescu D. Comparative effects of boric acid and calcium fructoborate on breast cancer cells. Biol Trace Elem Res. 2008; 122(3): 197-205.
  • Farhadi P, Yarani R, Dokaneheifard S, Mansouri K. The emerging role of targeting cancer metabolism for cancer therapy. Tumour Biol. 2020; 42(10): 1010428320965284.
  • Hassannia B, Vandenabeele P, Berghe TV. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019; 35: 830-49.
  • Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017; 171(2): 273-85.
  • Wei R, Zhao Y, Wang J, Yang X, Li S, Wang Y, et al. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells. Int J Biol Sci. 2021; 17(11): 2703-17.
  • Liu L, Yao H, Zhou X, Chen J, Chen G, Shi X, et al. MiR-15a-3p regulates ferroptosis via targeting glutathione peroxidase GPX4 in colorectal cancer. Mol Carcinog. 2022; 61(3): 301-10.

Cytotoxic Effects of Borax via GPx4/ACSL4 Signaling Pathway in Colorectal Cancer Cells

Yıl 2023, Cilt: 13 Sayı: 1, 54 - 60, 20.01.2023
https://doi.org/10.33631/sabd.1180766

Öz

Aim: Colorectal cancer (CRC) ranks third in terms of malignancy and second in cancer-related deaths, accounting for approximately 10% of cancer-related deaths. Ferroptosis is a potential iron-induced cell death pathway that could increase the anti-cancer efficacy of therapeutics in preventing drug resistance in the treatment of many cancers, including CRC. In this study, we aimed to investigate the anti-proliferative effects of borax via ferroptosis signaling pathway in CRC cells.
Material and Methods: Firstly, we determined the cytotoxic concentrations of borax (range 0 to 64 mM) with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Subsequently, glutathione peroxidase 4 (GPx4), acyl-CoA synthetase long chain family member 4 (ACSL4), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) levels were determined in HCT-116 cells incubated with cytotoxic borax concentrations for 24 hours.
Results: Borax at 1 and 4 mM concentrations did not affect cell viability, while borax at 8 mM and above concentrations significantly reduced viability in HTC-116 cells (p<0.05). According to MTT results, IC25 and IC50 concentrations of borax were determined as 12.5 mM and 20.8 mM, respectively. In HTC-116 cells, exposure to 12.5, 16.2, and 20.8 mM borax for 24 hours resulted in a concentration-dependent decrease in GPx4 levels and an increase in ACSL4 levels. We also found that increased borax administration to HTC-116 cells caused lipid peroxidation and DNA damage with a significant increase in MDA and 8-OHdG levels compared to control (p<0.05).
Conclusion: In line with our experimental data, borax showed anti-proliferative effects by inducing ferroptosis as a potential anti-cancer agent in human CRC cells.

Kaynakça

  • Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019; 394(10207): 1467-80.
  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394-424.
  • Henrikson NB, Webber EM, Goddard KA, Scrol A, Piper M, Williams MS, et al. Family history and the natural history of colorectal cancer: systematic review. Genet Med. 2015; 17(9): 702-12.
  • Schoen RE, Razzak A, Yu KJ, Berndt SI, Firl K, Riley TL, et al. Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer. Gastroenterology. 2015; 149(6): 1438-45.
  • Mishra J, Drummond J, Quazi SH, Karanki SS, Shaw JJ, Chen B, et al. Prospective of colon cancer treatments and scope for combinatorial approach to enhanced cancer cell apoptosis. Crit Rev Oncol Hematol. 2013; 86(3): 232-50.
  • DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014; 64(4): 252-71.
  • Dixon SJ. Ferroptosis: bug or feature? Immunol Rev. 2017; 277: 150-7.
  • Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016; 73: 2195-209.
  • Bano I, Horky P, Abbas SQ, Majid M, Bilal AHM, Ali F, et al. Ferroptosis: A new road towards cancer management. Molecules. 2022; 27(7): 2129.
  • Guo C, Liu P, Deng G, Han Y, Chen Y, Cai C, et al. Honokiol induces ferroptosis in colon cancer cells by regulating GPX4 activity. Am J Cancer Res. 2021; 11(6): 3039-54.
  • Yılmaz S, Ustundag A, Cemiloglu Ulker O, Duydu Y. Protective effect of boric acid on oxidative DNA damage in chinese hamster lung fibroblast V79 cell lines. Cell J. 2016; 17(4): 748-54.
  • Turkez H, Geyikoglu F, Tatar A, Keles MS, Kaplan I. The effects of some boron compounds against heavy metal toxicity in human blood. Exp Toxicol Pathol. 2012; 64(1-2): 93-101.
  • Kar F, Hacioglu C, Senturk H, Donmez DB, Kanbak G. The role of oxidative stress, renal inflammation, and apoptosis in post ischemic reperfusion ınjury of kidney tissue: the protective effect of dose-dependent boric acid administration. Biol Trace Elem Res. 2020; 195(1): 150-8.
  • Özyarım ŞC, Karabağ Çoban F. Investigation of the apoptotic and antiproliferative effects of boron on CCL-233 human colon cancer cells. Cell J. 2021; 23(4): 429-34.
  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1): 265-75.
  • Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer ıncidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol. 2017; 3(4): 524-48.
  • Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet. 2010; 375(9719): 1030-47.
  • Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: A Review. JAMA. 2021; 325(7): 669-85.
  • Rajamanickam S, Agarwal R. Natural products and colon cancer: current status and future prospects. Drug Dev Res. 2008; 69(7): 460-71.
  • Hadrup N, Frederiksen M, Sharma AK. Toxicity of boric acid, borax and other boron containing compounds: A review. Regul Toxicol Pharmacol. 2021; 121: 104873.
  • Yang W, Gao X, Wang B. Boronic acid compounds as potential pharmaceutical agents. Med Res Rev. 2003; 23(3): 346-68.
  • Deshayes S, Cabral H, Ishii T, Miura Y, Kobayashi S, Yamashita T, et al. Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J Am Chem Soc. 2013; 135(41): 15501-7.
  • 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.
  • Wade TB, Eckhert CD. Boric acid inhibits human prostate can- cer cell proliferation. Cancer Lett. 2004; 216(1): 21-9.
  • 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.
  • 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. Biol Trace Elem Res. 2020; 193(2): 400-9.
  • 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.
  • 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): 153-60.
  • Scorei R, Ciubar R, Ciofrangeanu CM, Mitran V, Cimpean A, Iordachescu D. Comparative effects of boric acid and calcium fructoborate on breast cancer cells. Biol Trace Elem Res. 2008; 122(3): 197-205.
  • Farhadi P, Yarani R, Dokaneheifard S, Mansouri K. The emerging role of targeting cancer metabolism for cancer therapy. Tumour Biol. 2020; 42(10): 1010428320965284.
  • Hassannia B, Vandenabeele P, Berghe TV. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019; 35: 830-49.
  • Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017; 171(2): 273-85.
  • Wei R, Zhao Y, Wang J, Yang X, Li S, Wang Y, et al. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells. Int J Biol Sci. 2021; 17(11): 2703-17.
  • Liu L, Yao H, Zhou X, Chen J, Chen G, Shi X, et al. MiR-15a-3p regulates ferroptosis via targeting glutathione peroxidase GPX4 in colorectal cancer. Mol Carcinog. 2022; 61(3): 301-10.
Toplam 34 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Klinik Tıp Bilimleri
Bölüm Araştırma Makaleleri
Yazarlar

Ceyhan Hacıoğlu 0000-0002-0993-6118

Fatih Davran 0000-0002-6086-6602

Yayımlanma Tarihi 20 Ocak 2023
Gönderilme Tarihi 27 Eylül 2022
Yayımlandığı Sayı Yıl 2023 Cilt: 13 Sayı: 1

Kaynak Göster

Vancouver Hacıoğlu C, Davran F. Kolorektal Kanser Hücrelerinde Boraksın Gpx4/ACSL4 Sinyal Yolu Aracılığıyla Sitotoksik Etkileri. SABD. 2023;13(1):54-60.