Çiğdem Ekin : 0000-0002-0914-1286

Neslihan Tekin Karacaer : 0000-0002-0091-6428

Mehtap Tarhan Karaoğlan : 0000-0002-0033-6378

İbrahim Örün : 0000-0002-7099-5969

Kamile Öztürk : 0000-0002-7228-0684.


Background: This study aimed to investigate the possible apoptotic role of bortezomib (BMZ) on pancreatic islets of streptozotocin (STZ)-induced diabetic rats.

Methods: Sprague-Dawley rats were divided into groups that were administered BMZ alone or in combination with STZ. To evaluate the effect of BMZ on the development of diabetes, blood glucose levels were measured regularly in the animals. Islet cell viability was determined by staining the islets with fluorescein diacetate and propidium iodide. Expression of the Bcl-2 and bax genes was determined in islet cells by quantitative real-time polymerase chain reaction.

Results: Administering STZ-induced hyperglycemia in the rats reduced the viability of islet cells and the bcl-2/bax ratio. In the group administered BMZ alone, the bcl-2/bax gene expression rate in islets increased significantly compared to the control group. BMZ co-administered with STZ significantly increased islet cell viability and the bcl-2/bax ratio compared to the diabetic group.

Conclusions: This study demonstrates that BMZ may protect pancreatic islet cells from apoptosis by increasing islet viability and upregulating the bcl-2/bax gene expression ratio, even though it failed to protect against the destructive effect of STZ.


  1. Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik DL. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: Many differences, few similarities. Diabetes. 2005;54 Suppl 2:S97–107.
  2. Ortis F, Pirot P, Naamane N, Kreins AY, Rasschaert J, Moore F, et al. Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells. Diabetologia. 2008;51:1213–25.
  3. Melloul D. Role of NF-kappaB in beta-cell death. Biochem Soc Trans. 2008;36:334–9.
  4. Karin M, Yamamoto Y, Wang QM. The IKK NF-kappa B system: A treasure trove for drug development. Nat Rev Drug Discov. 2004;3:17–26.
  5. Perkins ND. The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer. 2012;12:121–32.
  6. Eldor R, Abel R, Sever D, Sadoun G, Peled A, Sionov R, et al. Inhibition of nuclear factor-κB activation in pancreatic β-cells has a protective effect on allogeneic pancreatic islet graft survival. PLoS One. 2013;8:e56924.
  7. Takahashi T, Matsumoto S, Matsushita M, Kamachi H, Tsuruga Y, Kasai H, et al. Donor pretreatment with DHMEQ improves islet transplantation. J Surg Res. 2010;163:e23–34.
  8. Mujtaba T, Dou QP. Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med. 2011;12:471–80.
  9. Adams J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell. 2004;5:417–21.
  10. Mondanelli G, Albini E, Pallotta MT, Volpi C, Chatenoud L, Kuhn C, et al. The proteasome ınhibitor bortezomib controls ındoleamine 2,3-dioxygenase 1 breakdown and restores ımmune regulation in autoimmune diabetes. Front Immunol. 2017;8:428.
  11. Størling J, Allaman-Pillet N, Karlsen AE, Billestrup N, Bonny C, Mandrup-Poulsen T. Antitumorigenic effect of proteasome inhibitors on insulinoma cells. Endocrinology. 2005;146:1718–26.
  12. Litwak SA, Wali JA, Pappas EG, Saadi H, Stanley WJ, Varanasi LC, et al. Lipotoxic stress ınduces pancreatic β-Cell apoptosis through modulation of Bcl-2 proteins by the ubiquitin-proteasome system. J Diabetes Res. 2015;2015:280615.
  13. López-Avalos MD, Duvivier-Kali VF, Xu G, Bonner-Weir S, Sharma A, Weir GC. Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets. Diabetes. 2006;55:1223–31.
  14. Weisberg S, Leibel R, Tortoriello DV. Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice. Nutr Diabetes. 2016;6:e205.
  15. Furman BL. Streptozotocin-ınduced diabetic models in mice and rats. Curr Protoc Pharmacol. 2015;70:5.47.1–20.
  16. Hemeryck A, Geerts R, Monbaliu J, Hassler S, Verhaeghe T, Diels L, et al. Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14 C-bortezomib. Cancer Chemother Pharmacol. 2007;60:777–87.
  17. Feyat MS, Mercan S, Calısır E, Boyuk FG, Alparslan Pinarli F, Yesilyurt A, et al. Pancreatic beta cell purification by flow cytometer and a modified rat pancreatic islet cell isolation method. Niche. 2014;3:1–4.
  18. Dagli Gul AS, Fadillioglu E, Karabulut I, Yesilyurt A, Delibasi T. The effects of oral carvacrol treatment against H2O2 induced injury on isolated pancreas islet cells of rats. Islets. 2013;5:149–55.
  19. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.
  20. Kane RC, Dagher R, Farrell A, Ko CW, Sridhara R, Justice R, et al. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res. 2007;13:5291–4.
  21. King AJ. The use of animal models in diabetes research. Br J Pharmacol. 2012;166:877–94.
  22. Eleazu CO, Eleazu KC, Chukwuma S, Essien UN. Review of the mechanism of cell death resulting from streptozotocin challenge in experimental animals, its practical use and potential risk to humans. J Diabetes Metab Disord. 2013;12:60.
  23. Zhang Y, Zhang Y, Bone RN, Cui W, Peng JB, Siegal GP, et al. Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin. PLoS One. 2012;7:e36675.
  24. Zimmermann KC, Bonzon C, Green DR. The machinery of programmed cell death. Pharmacol Ther. 2001;92:57–70.
  25. Eizirik DL, Mandrup-Poulsen T. A choice of death--the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia. 2001;44:2115–33.
  26. McKenzie MD, Carrington EM, Kaufmann T, Strasser A, Huang DC, Kay TW, et al. Proapoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic beta-cells. Diabetes. 2008;57:1284–92.
  27. San Miguel J, Bladé J, Boccadoro M, Cavenagh J, Glasmacher A, Jagannath S, et al. A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist. 2006;11:51–61.
  28. Hofmeister-Brix A, Lenzen S, Baltrusch S. The ubiquitin-proteasome system regulates the stability and activity of the glucose sensor glucokinase in pancreatic β-cells. Biochem J. 2013;456:173–84.
  29. Buac D, Shen M, Schmitt S, Kona FR, Deshmukh R, Zhang Z, et al. From bortezomib to other inhibitors of the proteasome and beyond. Curr Pharm Des. 2013;19:4025–38.
  30. Krętowski R, Borzym-Kluczyk M, Cechowska-Pasko M. Efficient induction of apoptosis by proteasome inhibitor: Bortezomib in the human breast cancer cell line MDA-MB-231. Mol Cell Biochem. 2014;389:177–85.

Creative Commons License

Creative Commons Attribution-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Share Alike 3.0 License.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.