Journals / Bozok Tıp Dergisi / 2026 / Cilt: 16 Sayı: 2

Effect of Rapamycin and 3-Methyladenine on Heat shock proteins in Cisplatin-induced Hepatotoxicity

Sisplatin kaynaklı hepatotoksisitede Rapamisin ve 3-Metiladenin'in Isı şoku proteinleri üzerindeki etkisi

Derya Karabulut(ERCIYES UNIVERSITY)
Nurhan Kuloğlu(NİĞDE ÖMER HALİSDEMİR ÜNİVERSİTESİ)0000-0002-1199-2784
Pages
215–223
Publication Date
2026-06-15
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AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

As a result, Rapamycin is more effective than 3-Methyladenine on HSPs in Cisplatin toxicity.

📌 3 Key Takeaways

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Objective & Hypothesis:Purpose: This study aimed to investigate the effects of autophagy activator (rapamycin) and autophagy inhibitor (3-methyladenine) on heat shock proteins (HSP) in cisplatin-induced hepatotoxicity.
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Key Findings & Data:Materials and Methods: Wistar albino rats (28) in the study were divided into four equal groups.
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Conclusion & Impact:As a result, Rapamycin is more effective than 3-Methyladenine on HSPs in Cisplatin toxicity.
🔬Design:Araştırma Makalesi
📍Scope:Comprehensive Sample
⚙️Variables:Isı şoku proteinleri · sisplatin · rapamisin

Abstract

Purpose: This study aimed to investigate the effects of autophagy activator (rapamycin) and autophagy inhibitor (3-methyladenine) on heat shock proteins (HSP) in cisplatin-induced hepatotoxicity. Materials and Methods: Wistar albino rats (28) in the study were divided into four equal groups. Control group, Cisplatin group; On day 7 of the experiment, a single dose of 8 mg/kg intraperitoneal (ip) cisplatin was administered, Rapamycin+Cisplatin (Rapamycin group); Starting from the 1st day of the experiment, rapamycin 2 mg/kg(ip) was administered once a day for 15 days, 8 mg/kg(ip) single-dose cisplatin was administered on the 7th day, 3-methyladenine+Cisplatin (3-Methyladenine group) 15 mg/kg( ip) was administered once a day for 15 days, 8 mg/kg(ip) single-dose of cisplatin was administered on the 7th day. Routine histological techniques were applied for liver tissues. Immunohistochemistry staining was performed to identify HSPs. TUNEL was performed to demonstrate apoptosis. Results: All HSPs in the cisplatin group were statistically increased compared to the control. Rapamycin resulted in decreased expression of all HSPs, which was increased by cis. 3-Methyladenine was less effective in HSPs compared to Rapamycin. TUNEL-positive cells increased statistically in the Cisplatin group. Rapamycin was similar to the control group. TUNEL-positive cells did not change in the 3-methyladenine group. Conclusion: We think that Rapamycin reduces both HSPs and related cell death by contributing to the reduction of Cisplatin-induced oxidative stress in the tissue. Inhibition of autophagy with 3-Methyladenine in tissue causes increased expression of Cisplatin-induced HSPs. As a result, Rapamycin is more effective than 3-Methyladenine on HSPs in Cisplatin toxicity.

Özet

Amaç: Bu çalışmanın amacı, otofaji aktivatörü (rapamisin) ve otofaji inhibitörünün (3-metiladenin) sisplatin kaynaklı hepatotoksisitede ısı şoku proteinleri (HSP) üzerindeki etkilerini araştırmaktı. Gereç ve Yöntem: Çalışmadaki Wistar albino sıçanları (28) dört eşit gruba ayrıldı. Kontrol grubu, Sisplatin grubu; Deneyin 7. gününde, tek doz 8 mg/kg intraperitoneal (ip) sisplatin uygulandı, Rapamisin+Sisplatin (Rapamisin grubu); Deneyin 1. gününden itibaren, rapamisin 2 mg/kg(ip) günde bir kez 15 gün boyunca uygulandı, 8 mg/kg(ip) tek doz sisplatin 7. günde uygulandı, 3-metiladenin+Sisplatin (3-Metiladenin grubu) 15 mg/kg(ip) günde bir kez 15 gün boyunca uygulandı, 8 mg/kg(ip) tek doz sisplatin 7. günde uygulandı. Karaciğer dokuları için rutin histolojik teknikler uygulandı. HSP'leri tanımlamak için immünohistokimya boyama yapıldı. Apoptozu göstermek için TUNEL yapıldı. Bulgular: Sisplatin grubundaki tüm HSP'ler kontrole kıyasla istatistiksel olarak arttı. Rapamisin, cis tarafından artırılan tüm HSP'lerin ekspresyonunun azalmasına neden oldu. 3-Metiladenin, Rapamisin ile karşılaştırıldığında HSP'lerde daha az etkiliydi. TUNEL pozitif hücreler Cisplatin grubunda istatistiksel olarak arttı. Rapamisin kontrol grubuna benzerdi. TUNEL pozitif hücreler 3-metiladenin grubunda değişmedi. Sonuç: Rapamisin'in dokuda Cisplatin kaynaklı oksidatif stresin azaltılmasına katkıda bulunarak hem HSP'leri hem de ilgili hücre ölümünü azalttığını düşünüyoruz. Dokuda 3-Metiladenin ile otofaji inhibisyonu Cisplatin kaynaklı HSP'lerin ekspresyonunun artmasına neden olur. Sonuç olarak Rapamisin, Cisplatin toksisitesinde HSP'ler üzerinde 3-Metiladenin'den daha etkilidir.

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Cite This Article

Karabulut, D., Kuloğlu, N., Öztürk, E., Sayan, M., Kaymak, E., Akin, A. T., Öztürk, T. M., Yalçın, B. (2026). Effect of Rapamycin and 3-Methyladenine on Heat shock proteins in Cisplatin-induced Hepatotoxicity. Bozok Tıp Dergisi, Cilt: 16 Sayı: 2, 215–223. https://doi.org/10.16919/bozoktip.1819527

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References (39)

  1. Arrigo AP. Heat shock proteins as molecular chaperones. Med Sci (Paris). 2005;21(6-7):619-25.
  2. Kim HP, Morse D, Choi AM. Heat-shock proteins: new keys to the development of cytoprotective therapies. Expert Opin Ther Targets. 2006;10(5):759-69.
  3. De Maio A, Vazquez D. Extracellular heat shock proteins: a new location, a new function. Shock. 2013;40(4):239-46.
  4. Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat Shock Proteins and Cancer. Trends Pharmacol Sci. 2017;38(3):226-56.
  5. Dokladny K, Myers OB, Moseley PL. Heat shock response and autophagy--cooperation and control. Autophagy. 2015;11(2):200-13.
  6. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451(7182):1069-75.
  7. Pasquier B. Autophagy inhibitors. Cell Mol Life Sci. 2016;73(5):985-1001.
  8. Sato M, Seki T, Konno A, Hirai H, Kurauchi Y, Hisatsune A, et al. Rapamycin activates mammalian microautophagy. J Pharmacol Sci. 2019;140(2):201-4.
  9. Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelárová H, Meijer AJ. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem. 1997;243(1-2):240-6.
  10. Ghosh S. Cisplatin: The first metal based anticancer drug. Bioorg Chem. 2019;88:102925.
  11. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364-78.
  12. Musio F, Carome MA, Bohen EM, Sabnis S, Yuan CM. Effect of glycine on cisplatin nephrotoxicity and heat-shock protein 70 expression in the rat kidney. Ren Fail. 1997;19(1):33-46.
  13. Baker TG, Roy S, Brandon CS, Kramarenko IK, Francis SP, Taleb M, et al. Heat shock protein-mediated protection against Cisplatin-induced hair cell death. J Assoc Res Otolaryngol. 2015;16(1):67-80.
  14. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31(15):1869-83.
  15. Guo H, Ren H, Li J, Hao M, Hao J, Ren H, et al. TIPE2 suppressed cisplatin resistance by inducing autophagy via mTOR signalling pathway. Exp Mol Pathol. 2020;113:104367.
  16. Niu C, Ma M, Han X, Wang Z, Li H. Hyperin protects against cisplatin-induced liver injury in mice. Acta Cir Bras. 2017;32(8):633-40.
  17. El-Shitany NA, Eid B. Proanthocyanidin protects against cisplatin-induced oxidative liver damage through inhibition of inflammation and NF-κβ/TLR-4 pathway. Environ Toxicol. 2017;32(7):1952-63.
  18. Deger N, Ozmen R, Karabulut D. Thymoquinone regulates nitric oxide synthase enzymes and receptor-interacting serine-threonine kinases in isoproterenol-induced myocardial infarcted rats. Chemico-biological interactions. 2022;365:110090.
  19. Öztürk E, Kaymak E, Akin AT, Karabulut D, Ünsal HM, Yakan B. Thymoquinone is a protective agent that reduces the negative effects of doxorubicin in rat testis. Hum Exp Toxicol. 2020:960327120924108.
  20. Massey AC, Zhang C, Cuervo AM. Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol. 2006;73:205-35.
  21. Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem. 2018;293(15):5414-24.
  22. Madrigal-Matute J, Cuervo AM. Regulation of Liver Metabolism by Autophagy. Gastroenterology. 2016;150(2):328-39.
  23. Morán Luengo T, Mayer MP, Rüdiger SGD. The Hsp70-Hsp90 Chaperone Cascade in Protein Folding. Trends Cell Biol. 2019;29(2):164-77.
  24. Genest O, Wickner S, Doyle SM. Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling. J Biol Chem. 2019;294(6):2109-20.
  25. Caruso Bavisotto C, Alberti G, Vitale AM, Paladino L, Campanella C, Rappa F, et al. Hsp60 Post-translational Modifications: Functional and Pathological Consequences. Front Mol Biosci. 2020;7:95.
  26. Nagata K. Hsp47: a collagen-specific molecular chaperone. Trends Biochem Sci. 1996;21(1):22-6.
  27. Ito S, Nagata K. Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone. Semin Cell Dev Biol. 2017;62:142-51.
  28. Qu X, Gao H, Tao L, Zhang Y, Zhai J, Song Y, et al. Autophagy inhibition-enhanced assembly of the NLRP3 inflammasome is associated with cisplatin-induced acute injury to the liver and kidneys in rats. J Biochem Mol Toxicol. 2018:e22208.
  29. Cardinal J, Pan P, Tsung A. Protective role of cisplatin in ischemic liver injury through induction of autophagy. Autophagy. 2009;5(8):1211-2.
  30. Su YC, Davuluri GV, Chen CH, Shiau DC, Chen CC, Chen CL, et al. Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma. PLoS One. 2016;11(2):e0148408.
  31. Liu J, Li Y, Yang X, Dong Y, Wu J, Chen M. Effects of ginkgol C17:1 on cisplatin-induced autophagy and apoptosis in HepG2 cells. Oncol Lett. 2018;15(1):1021-9.
  32. Takemura S, Azuma H, Osada-Oka M, Kubo S, Shibata T, Minamiyama Y. S-allyl-glutathione improves experimental liver fibrosis by regulating Kupffer cell activation in rats. Am J Physiol Gastrointest Liver Physiol. 2018;314(2):G150-g63.
  33. Zhang X, Zhang X, Huang W, Ge X. The role of heat shock proteins in the regulation of fibrotic diseases. Biomed Pharmacother. 2021;135:111067.
  34. Wang C, Zhang Y, Guo K, Wang N, Jin H, Liu Y, et al. Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential. Int J Cancer. 2016;138(8):1824-34.
  35. Nouri-Vaskeh M, Alizadeh L, Hajiasgharzadeh K, Mokhtarzadeh A, Halimi M, Baradaran B. The role of HSP90 molecular chaperones in hepatocellular carcinoma. J Cell Physiol. 2020;235(12):9110-20.
  36. Martinez-Lopez N, Singh R. Autophagy and Lipid Droplets in the Liver. Annu Rev Nutr. 2015;35:215-37.
  37. Wang B, Yang H, Fan Y, Yang Y, Cao W, Jia Y, et al. 3-Methyladenine ameliorates liver fibrosis through autophagy regulated by the NF-κB signaling pathways on hepatic stellate cell. Oncotarget. 2017;8(64):107603-11.
  38. Zhu W, Yu H, Jia M, Lin C, Yuan Z, Tan X, et al. Multi-targeting liposomal codelivery of cisplatin and rapamycin inhibits pancreatic cancer growth and metastasis through stromal modulation. Int J Pharm. 2023;644:123316.
  39. Zheng XY, Yang SM, Zhang R, Wang SM, Li GB, Zhou SW. Emodin-induced autophagy against cell apoptosis through the PI3K/AKT/mTOR pathway in human hepatocytes. Drug Des Devel Ther. 2019;13:3171-80.