Gallik Asit Kardiyomiyositlerde Sisplatin ile İndüklenen Apoptoz, Oksidatif Stres ve İnflamasyonu Azaltıyor

Öz

Amaç: Sisplatin (CIS), çeşitli kanserlerin tedavisinde uzun süredir tek başına veya kombinasyon halinde kullanılan güçlü bir kemoterapötik ajandır. Bununla birlikte, CIS'in çeşitli dokulardaki toksisitesi kullanımını sınırlamaktadır. Gallik asit (GAL) anti-enflamatuar, anti-mikrobiyal ve anti-tümör gibi özelliklere sahiptir. GAL'in geniş biyolojik özelliklere sahip olması ve antioksidan aktivite sergilemesi sebebiyle bu çalışmada GAL'in H9c2 kardiyomiyosit hücre hatlarında CIS kaynaklı kardiyotoksite üzerindeki etkisinin araştırılması amaçlanmıştır. Materyal ve Metot: Kontrol (CON) olarak H9c2 kardiyomiyosit hücreleri, CIS ve CIS ile birlikte GAL25, GAL50 kombinasyonları kullanılmıştır. Çalışmada yapılan analizlerde kardiyomiyosit hücrelerinde Total Antioksidan/Oksidan (TAS ve TOS) durumu, inflamasyon belirteçleri TNF α, IL 1β ve IL 6, lipid peroksidasyon düzeyleri, glutatyon (GSH) ve glutatyon peroksidaz (GSH-Px) enzim aktivitesi, reaktif oksijen türleri (ROS) ve kaspaz aktivitesi (Casp 3-9) belirlenmiştir. Bulgular: Sonuçlar, CIS tedavisinin kardiyomiyosit hücresinde toksisiteye neden olduğunu ve Casp 3-9, ROS, IL 1β, TNF α, IL 6, MDA ve TOS seviyelerini artırırken GSH-Px, GSH ve TAS seviyelerini azalttığını gösterdi. CIS tedavisi sonrasında kardiyomiyosit hücrelerinde artan inflamasyon ve bozulan oksidan/antioksidan dengesi GAL tedavisi ile düzenlenmiştir. Sonuç: GAL tedavisinin kardiyomiyosit hücrelerinde CIS kaynaklı kardiyotoksisite üzerinde koruyucu bir etkiye sahip olduğu bulunmuştur.

Anahtar Kelimeler

• Gallik asit
• H9c2 kardiyomiyosit
• kardiyotoksisite
• oksidatif stres
• sisplatin

Gallic Acid Attenuates Cisplatin-Induced Apoptosis, Oxidative Stress, and Inflammation in Cardiomyocytes

Abstract

Objective: Cisplatin (CIS) is a powerful chemotherapeutic agent that has long been used alone or in combination in the treatment of various cancers. However, the toxicity of CIS in various tissues limits its use. Gallic acid (GAL) has anti-microbial, anti-inflammatory, and anti-tumor properties. Since GAL has broad biological properties and exhibits antioxidant activity, this study aimed to investigate the effect of GAL on CIS-induced cardiotoxicity in H9c2 cardiomyocyte cell lines. Materials and Methods: H9c2 cardiomyocyte cells as control (CON), CIS, and GAL25, GAL50 in combination along with CIS were used. In the analyses made, glutathione (GSH) and glutathione peroxidase (GSH-Px) enzyme activity, lipid peroxidation levels, inflammation markers IL1β, IL 6, and TNF α, Total Oxidant/ Antioxidant (TOS and TAS) status, reactive oxygen species (ROS) and caspase (Casp 3-9) activity in the cells were determined. Results: CIS treatment caused cardiomyocyte cell toxicity and increased Casp 3-9, ROS, IL 1β, TNF α, IL 6, TOS, and MDA levels while decreasing GSH-Px, GSH, and TAS levels. Increased inflammation and impaired oxidant/antioxidant balance in cardiomyocyte cells after CIS treatment were regulated by GAL treatment. Conclusions: GAL treatment was found to have a protective effect on CIS-induced cardiotoxicity in cardiomyocyte cells.

Keywords

• Cardiotoxicity
• cisplatin
• gallic acid
• H9c2 cardiomyocyte
• oxidative stress

Kaynakça

1. Domingo IK, Latif A, Bhavsar AP. Pro-inflammatory signalling PRRopels cisplatin-induced toxicity. Int J Mol Sci. 2022;29(13):7227. doi:10.3390/ijms23137227
2. Wang SH, Tsai KL, Chou WC, et al. Quercetin mitigates cisplatin-induced oxidative damage and apoptosis in cardiomyocytes through Nrf2/HO-1 signaling pathway. Am J Chin Med. 2022;50(5):1281-1298. doi:10.1142/S0192415X22500537
3. Ayazoglu DE, Mentese A, Livaoglu A, Turkmen AN, Demir S. Ameliorative effect of gallic acid on cisplatin-induced ovarian toxicity in rats. Drug Chem Toxicol. 2023;46(1):97-103. doi:10.1080/01480545.2021.2011312
4. Li S, Lin Q, Shao X, et al. NLRP3 inflammasome inhibition attenuates cisplatin-induced renal fibrosis by decreasing oxidative stress and inflammation. Exp. Cell Res. 2019;383:111488. doi:10.1016/j.yexcr.2019.07.001
5. Altındağ F, Meydan I. Evaluation of protective effects of gallic acid on cisplatin-induced testicular and epididymal damage. Andrologia. 2021;53(10):e14189. doi:10.1111/and.14189
6. Gentilin E, Simoni E, Candito M, Cazzador D, Astolfi L. Cisplatin-induced ototoxicity: updates on molecular targets. Trends Mol. Med. 2019;25:1123–1132. doi:10.1016/j.molmed.2019.08.002
7. Tang C, Livingston MJ, Safirstein R, Dong Z. Cisplatin nephrotoxicity: new insights and therapeutic implications. Nat Rev Nephrol. 2023;19(1):53-72. doi:10.1038/s41581-022-00631-7
8. Xu J, Zhang B, Chu Z, Jiang F, Han J. Wogonin alleviates cisplatin-induced cardiotoxicity in mice via inhibiting gasdermin D-mediated pyroptosis. J Cardiovasc Pharmacol. 2021;78(4):597-603. doi:10.1097/FJC.0000000000001085

9. Xia J, Hu JN, Zhang RB, et al. Icariin exhibits protective effects on cisplatin-induced cardiotoxicity via ROS-mediated oxidative stress injury in vivo and in vitro. Phytomedicine. 2022;104:154331. doi:10.1016/j.phymed.2022.154331
10. Kahkeshani N, Farzaei F, Fotouhi M, et al. Pharmacological effects of gallic acid in health and diseases: A mechanistic review. Iranian journal of basic medical sciences. 2019;22(3):225–237. doi:10.22038/ijbms.2019.32806.7897
11. Doğan D, Meydan İ, Kömüroğlu AU. Protective effect of silymarin and gallic acid against cisplatin-induced nephrotoxicity and hepatotoxicity. Int J Clin Pract. 2022;16:6541026. doi:10.1155/2022/6541026
12. Dehghani MA, Shakiba MN, Moghimipour E, Khorsandi L, Atefi KM, Mahdavinia M. Protective effect of gallic acid and gallic acid-loaded Eudragit-RS 100 nanoparticles on cisplatin-induced mitochondrial dysfunction and inflammation in rat kidney. Biochim Biophys Acta Mol Basis Dis. 2020;1866(12):165911. doi:10.1016/j.bbadis.2020.165911
13. Han S, Bao L, Li W, et al. Gallic acid inhibits mesaconitine-activated TRPV1-channel-induced cardiotoxicity. Evid Based Complement Alternat Med. 2022;13:5731372. doi:10.1155/2022/5731372
14. Yazğan Y. Effect of gallic acid on PTZ-induced neurotoxıcıty, oxidative stress and inflammation in SH-SY5Y neuroblastoma cells. Acta Med. Alanya. 2024;8(1):10-17. doi:10.30565/medalanya.1415132
15. Yazğan B, Yazğan Y. Potent antioxidant alpha lipoic acid reduces STZ-induced oxidative stress and apoptosis levels in the erythrocytes and brain cells of diabetic rats. Journal of Cellular Neuroscience and Oxidative Stress. 2022;14(2):1085-1094. doi:10.37212/jcnos.1245152
16. Jia Y, Guo H, Cheng X, et al. Hesperidin protects against cisplatin-induced cardiotoxicity in mice by regulating the p62-Keap1-Nrf2 pathway. Food Funct. 2022;13(7):4205-4215. doi:10.1039/d2fo00298a
17. Qi L, Luo Q, Zhang Y, Jia F, Zhao Y, Wang F. Advances in toxicological research of the anticancer drug cisplatin. Chem Res Toxicol. 2019;32(8):1469-1486. doi:10.1021/acs.chemrestox.9b00204
18. Kohsaka T, Minagawa I, Morimoto M, et al. Efficacy of relaxin for cisplatininduced testicular dysfunction and epididymal spermatotoxicity. Basic and Clinical Andrology. 2020;30(1):3. doi: 101186/s12610-020-0101-y
19. Xia J, Hu JN, Zhang RB, et al. Icariin exhibits protective effects on cisplatin-induced cardiotoxicity via ROS-mediated oxidative stress injury in vivo and in vitro. Phytomedicine. 2022;104:154331. doi:10.1016/j.phymed.2022.154331
20. Abbasalipour H, Hajizadeh MA, Ranjbar M. Sumac and gallic acid-loaded nanophytosomes ameliorate hippocampal oxidative stress via regulation of Nrf2/Keap1 pathway in autistic rats. J Biochem Mol Toxicol. 2022;36(6):e23035. doi:10.1002/jbt.23035
21. Ibrahim MA, Albahlol IA, Wani FA, et al. Resveratrol protects against cisplatin-induced ovarian and uterine toxicity in female rats by attenuating oxidative stress, inflammation and apoptosis. Chem Biol Interact. 2021;338:109402. doi:10.1016/j.cbi.2021.109402
22. So H, Kim H, Lee JH, et al. Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-κB. JARO-J. Assoc. Res. Otolaryngol. 2007;8:338–355. doi:10.1007/s10162-007-0084-9
23. Kim HJ, Oh GS, Lee JH, et al. Cisplatin ototoxicity involves cy-tokines and STAT6 signaling network. Cell Res. 2011;21:944–956. doi:10.1038/cr.2011.27
24. Bai J, Zhang Y, Tang C, et al. Gallic acid: Pharmacological activities and molecular mechanisms involved in inflammation-related diseases. Biomed Pharmacother. 2021;133:110985. doi:10.1016/j.biopha.2020.110985
25. Ramezani AF, Badavi M, Dianat M, Mard SA, Ahangarpour A. Effects of gallic acid on hemodynamic parameters and infarct size after ischemia-reperfusion in isolated rat hearts with alloxan-induced diabetes. Biomed Pharmacother. 2017;96:612-618. doi:10.1016/j.biopha.2017.10.014
26. Qian P, Yan LJ, Li YQ, et al. Cyanidin ameliorates cisplatin-induced cardiotoxicity via inhibition of ROS-mediated apoptosis. Exp Ther Med. 2018;15(2):1959-1965. doi:10.3892/etm.2017.5617
27. Momeni Z, Danesh S, Ahmadpour M, et al. Protective roles and therapeutic effects of gallic acid in the treatment of cardiovascular diseases: current trends and future directions. Curr Med Chem, 2024;31(24):3733-3751. doi:10.2174/0109298673259299230921150030
28. Tanaka M, Sato A, Kishimoto Y, Mabashi AH, Kondo K, Iida K. Gallic acid inhibits lipid accumulation via AMPK pathway and suppresses apoptosis and macrophage-mediated inflammation in hepatocytes. Nutrients. 2020;12(5):1479. doi:10.3390/nu12051479
29. Ahlatci A. Investıgatıon of the amelıoratıve effects of gallic acid agaınst neurotoxicity caused by glutamate in C6 cells. Neuro-Cell Mol Res. 2024;1(1):7-13. doi:10.5281/zenodo.11471554