Meme Kanseri Hücrelerinde Eş Zamanlı Epigenetik ve Epitranskriptomik Müdahalenin Etkisi

Yıl 2024, , 505 - 521, 31.08.2024

Sevinç Yanar , Asuman Deveci Özkan , Merve Gülşen Bal Albayrak , Zeynep Betts

https://doi.org/10.38079/igusabder.1469350

Öz

Amaç: Dünya çapında önemli bir ölüm nedeni olmaya devam etmekte olan meme kanseri için yenilikçi tedavi yaklaşımlarının geliştirilmesi gerekmektedir. Epigenetik ve epitranskriptomik düzenleme, yeni tedaviler için umut verici yollar olarak ortaya çıkmıştır. Sodyum Butirat (NaB) ve Meklofenamik Asit (MFA), epigenetik ve epitranskriptomik modülasyondaki ilgili rollerinden dolayı dikkat çekmektedir. Bir histon deasetilaz inhibitörü olan NaB, kromatin yeniden yapılanması ve gen ekspresyonunda kritik bir düzenleyici olarak görev yapmaktadır. MFA'nın ise FTO enziminin güçlü bir inhibitörü olduğu tespit edilmiştir. Bu inhibitör potansiyel, epitranskriptomik düzenlemedeki rolünü göstermektedir. Bu çalışma, MFA ve NaB'nin ayrı ayrı ve kombinasyon halinde MCF7 meme kanseri hücre hattı üzerindeki potansiyel etkilerini araştırmayı amaçlanmıştır.
Yöntem: MFA ve NaB kombinasyon tedavisinin sitotoksik ve apoptotik etkilerini araştırmak amacıyla hücre canlılığı analizi, Annexin V analizi ve Akridin Orange/DAPI boyaması yapılmıştır.
Bulgular: Sonuçlar kombinasyon tedavisinin beklenmedik şekilde antagonistik etki gösterdiğini ortaya çıkarmıştır. MFA ve NaB’ın tek başına uygulamasına kıyasla kombinasyon halinde uygulanması hücre canlılığında kayda değer bir artışa ve apoptotik yanıtın azalmasına neden olmuştur. En güçlü antagonistik etki, hücreler 48 saat boyunca 100 μM MFA ve 2 mM NaB ile inkübe edildiğinde gözlemlenmiştir (CI= 88,3).
Sonuç: Bu çalışma, ilk kez, meklofenamik asit ile sodyum bütirat arasındaki karmaşık etkileşime ışık tutmuş ve MCF7 meme kanseri hücreleri üzerindeki beklenmedik antagonistik etkisini ortaya koymuştur. Bu bulgular, geleneksel sinerjistik etkileşim kavramlarına meydan okumakla birlikte meme kanseri tedavisinde ilaç kombinasyonlarının karmaşıklığının altını çizmektedir.

Anahtar Kelimeler

Meme kanseri, meklofenamik asit, sodyum bütirat, kombinasyon tedavisi, antagonizm

The Impact of Simultaneous Epigenetic and Epitranscriptomic Intervention in Breast Cancer Cells

Öz

Aim: Breast cancer remains a significant cause of mortality worldwide, necessitating the development of innovative therapeutic approaches. Epigenetic and epitranscriptomic regulation have emerged as promising avenues for novel treatments. Sodium Butyrate (NaB) and Meclofenamic Acid (MFA) have gained attention for their respective roles in epigenetic and epitranscriptomic modulation. NaB, a histone deacetylase inhibitor, serves as a critical regulator of chromatin remodeling and gene expression. MFA has been identified to be a potent inhibitor of the FTO enzyme. This inhibitory potential marks its role in epitranscriptomic regulation. This study aimed to investigate the potential effects of MFA and NaB, individually and in combination, on the MCF7 breast cancer cell line.
Method: In order to investigate the cytotoxic and apoptotic effects of the combination treatment of MFA and NaB, cell viability assay, Annexin V analysis and Acridine Orange/DAPI staining were executed.
Results: The results revealed that the combination treatment unexpectedly exhibited antagonistic effects. This was evidenced by a remarkable increase in cell viability and a decreased apoptotic response compared to individual treatments. The strongest antagonistic effect was observed when the cells were treated with 100 μM MFA and 2 mM NaB for a period of 48 hours (CI = 88.3).
Conclusion: This study, for the first time, sheds light on the complex interaction between meclofenamic acid and sodium butyrate that reveals an unexpected antagonistic effect on MCF7 breast cancer cells. These findings challenge conventional concepts of synergistic interactions and underscore the complexity of drug combinations in breast cancer treatment.

Anahtar Kelimeler

Breast cancer, meclofenamic acid, sodium butyrate, combined therapy, antagonism

Kaynakça

• 1. Giaquinto AN, Sung H, Miller KD, et al. Breast cancer statistics. CA: A Cancer J Clin. 2022;72(6):524-541. doi: 10.3322/caac.21754.
• 2. López J, Añazco-Guenkova AM, Monteagudo-García Ó, et al. Epigenetic and epitranscriptomic control in prostate cancer. Genes. 2022;13(2):378. doi: 10.3390/genes13020378.
• 3. Sarvari P, Sarvari P, Ramírez-Díaz I, et al. Advances of epigenetic biomarkers and epigenome editing for early diagnosis in breast cancer. Int J Mol Sci. 2022;23(17):9521. doi: 10.3390/ijms23179521.
• 4. Xi Y, Jing Z, Wei W, et al. Inhibitory effect of sodium butyrate on colorectal cancer cells and construction of the related molecular network. BMC Cancer. 2021;21(1):127. doi: 10.1186/s12885-021-07845-1.
• 5. Kaźmierczak-Siedlecka K, Marano L, Merola E, et al. Sodium butyrate in both prevention and supportive treatment of colorectal cancer. Front Cell Infect Microbiol. 2022;12:1023806. doi: 10.3389/fcimb.2022.1023806.
• 6. Zhang K, Ji X, Song Z, et al. Butyrate inhibits the mitochondrial complex Ι to mediate mitochondria-dependent apoptosis of cervical cancer cells. BMC Complement Med Ther. 2023;23(1):212. doi: 10.1186/s12906-023-04043-3.
• 7. Salimi V, Shahsavari Z, Safizadeh B, et al. Sodium butyrate promotes apoptosis in breast cancer cells through reactive oxygen species (ROS) formation and mitochondrial impairment. Lipids Heal Dis. 2017;16(1):208. doi: 10.1186/s12944-017-0593-4.
• 8. Ho TCS, Chan AHY, Ganesan A. Thirty years of HDAC inhibitors: 2020 insight and hindsight. J Med Chem. 2020;63(21):12460-12484. doi: 10.1021/acs.jmedchem.0c00830.
• 9. Suraweera A, O’Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi. Front Oncol. 2018;8:92. doi: 10.3389/fonc.2018.00092.
• 10. Saglam BS, Kanli A, Yanar S, et al. Investigation of the effect of meclofenamic acid on the proteome of LNCaP cells reveals changes in alternative polyadenylation and splicing machinery. Méd Oncol. 2022;39(12):190. doi: 10.1007/s12032-022-01795-9.
• 11. Huang Y, Yan J, Li Q, et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 2015;43(1):373-384. doi: 10.1093/nar/gku1276.
• 12. Yanar S, Kasap M, Kanli A, et al. Proteomics analysis of meclofenamic acid‐treated small cell lung carcinoma cells revealed changes in cellular energy metabolism for cancer cell survival. J Biochem Mol Toxicol. 2023;37(4):e23289. doi: 10.1002/jbt.23289.
• 13. Soriano-Hernandez AD, Madrigal-Pérez D, Galvan-Salazar HR, et al. Anti-inflammatory drugs and uterine cervical cancer cells: Antineoplastic effect of meclofenamic acid. Oncol Lett. 2015;10(4):2574-2578. doi: 10.3892/ol.2015.3580.
• 14. Delgado-Enciso I, Soriano-Hernández AD, Rodriguez-Hernandez A, et al. Histological changes caused by meclofenamic acid in androgen independent prostate cancer tumors: Evaluation in a mouse model. Int Braz J Urol : Off J Braz Soc Urol. 2015;41(5):1002-1007. doi: 10.1590/s1677-5538.ibju.2013.00186.
• 15. Chou T, Talalay P. Generalized equations for the analysis of inhibitions of Michaelis‐Menten and higher‐order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem. 1981;115(1):207-216. doi: 10.1111/j.1432-1033.1981.tb06218.x.
• 16. Walker JH, Boustead CM, Koster JJ et al. Annexin v, a calcium-dependent phospholipid-binding protein. Biochem Soc Trans. 1992;20(4):828-833. doi: 10.1042/bst0200828.
• 17. Betts Z, Ozkan AD, Yuksel B, et al. Investigation of the combined cytotoxicity induced by sodium butyrate and a flavonoid quercetin treatment on MCF-7 breast cancer cells. J Toxicol Environ Heal, Part A. 2023;86(22):833-845. doi:10.1080/15287394.2023.2254807.
• 18. Jia J, Zhu F, Ma X, et al. Mechanisms of drug combinations: Interaction and network perspectives. Nat Rev Drug Discov. 2009;8(2):111-128. doi: 10.1038/nrd2683.
• 19. Pelicano H, Carew JS, McQueen TJ, et al. Targeting Hsp90 by 17-AAG in leukemia cells: Mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C. Leukemia. 2006;20(4):610-619. doi: 10.1038/sj.leu.2404140.
• 20. Yanar S, Kanli A, Kasap M, et al. Synergistic effect of a nonsteroidal anti-inflammatory drug in combination with topotecan on small cell lung cancer cells. Mol Biol Rep. 2024;51(1):145. doi: 10.1007/s11033-023-09055-3.
• 21. Hałasa M, Łuszczki JJ, Dmoszyńska-Graniczka M, et al. Antagonistic interaction between histone deacetylase inhibitor: Cambinol and cisplatin—an isobolographic analysis in breast cancer in vitro models. Int J Mol Sci. 2021;22(16):8573. doi: 10.3390/ijms22168573.
• 22. Wawruszak A, Luszczki JJ, Grabarska A, et al. Assessment of interactions between cisplatin and two histone deacetylase inhibitors in MCF7, T47D and MDA-MB-231 human breast cancer cell lines – an isobolographic analysis. PLoS ONE. 2015;10(11):e0143013. doi: 10.1371/journal.pone.0143013.
• 23. Ibrahim AB, Zaki HF, Wadie W, et al. Simvastatin evokes an unpredicted antagonism for tamoxifen in MCF-7 breast cancer cells. Cancer Manag Res. 2019;11:10011-10028. doi: 10.2147/cmar.s218668.
• 24. El-Awady RA, Saleh EM, Ezz M, et al. Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Toxicol Appl Pharmacol. 2011;255(3):271-286. doi: 10.1016/j.taap.2011.06.019.
• 25. Sargazi S, Kooshkaki O, Reza JZ, et al. Mild antagonistic effect of Valproic acid in combination with AZD2461 in MCF-7 breast cancer cells. Méd J Islam Repub Iran. 2019;33:29-29. doi: 10.34171/mjiri.33.29.
• 26. Wawruszak A, Luszczki J, Okon E, et al. Antagonistic pharmacological interaction between sirtuin inhibitor cambinol and paclitaxel in triple-negative breast cancer cell lines: an isobolographic analysis. Int J Mol Sci. 2022;23(12):6458. doi: 10.3390/ijms23126458.
• 27. Sekine Y, Nakayama H, Miyazawa Y, et al. Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC-3 cells via an AKR1C3 mechanism. Oncol Lett. 2018;15(3):3167-3172. doi: 10.3892/ol.2017.7721.
• 28. Shuwen H, Yangyanqiu W, Jian C, et al. Synergistic effect of sodium butyrate and oxaliplatin on colorectal cancer. Transl Oncol. 2022;27:101598.
• 29. Wen L, Pan X, Yu Y, et al. Down-regulation of FTO promotes proliferation and migration, and protects bladder cancer cells from cisplatin-induced cytotoxicity. BMC Urol. 2020;20(1):39. doi: 10.1186/s12894-020-00612-7.
• 30. Cui Q, Wang C, Zeng L, et al. Editorial: Novel small-molecule agents in overcoming multidrug resistance in cancers. Front Chem. 2022;10:921985.
• 31. Li H, Song Y, He Z, et al. Meclofenamic acid reduces reactive oxygen species accumulation and apoptosis, inhibits excessive autophagy, and protects hair cell-like HEI-OC1 cells from cisplatin-induced damage. Front Cell Neurosci. 2018;12:139.
• 32. Zhou Q, Dalgard CL, Wynder C, et al. Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells. BMC Neurosci. 2011;12(1):50-50. doi: 10.1186/1471-2202-12-50.
• 33. Li Y, He P, Liu Y, et al. Combining sodium butyrate with cisplatin increases the apoptosis of gastric cancer in vivo and in vitro via the mitochondrial apoptosis pathway. Front Pharmacol. 2021;12:708093. doi: 10.3389/fphar.2021.708093.
• 34. Galfi P, Jakus J, Molnar T, et al. Divergent effects of resveratrol, a polyphenolic phytostilbene, on free radical levels and type of cell death induced by the histone deacetylase inhibitors butyrate and trichostatin A. J Steroid Biochem Mol Biol. 2005;94(1-3):39-47. doi: 10.1016/j.jsbmb.2004.12.019.