Research Article Elucidation of Molecular Mechanisms of Streptozotocin-Induced Oxidative Stress, Apoptosis, and Mitochondrial Dysfunction in Rin-5F Pancreatic β-Cells Arwa M. T. Al Nahdi, Annie John, and Haider Raza Department of Biochemistry, College of Medicine and Health Sciences (CMHS), UAE University, Al Ain, UAE Correspondence should be addressed to Haider Raza; h.raza@uaeu.ac.ae Received 26 April 2017; Revised 12 June 2017; Accepted 2 July 2017; Published 6 August 2017 Academic Editor: Maik Hüttemann Copyright © 2017 Arwa M. T. Al Nahdi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Streptozotocin is a pancreatic beta-cell-specific cytotoxin and is widely used to induce experimental type 1 diabetes in rodent models. The precise molecular mechanism of STZ cytotoxicity is however not clear. Studies have suggested that STZ is preferably absorbed by insulin-secreting β-cells and induces cytotoxicity by producing reactive oxygen species/reactive nitrogen species (ROS/RNS). In the present study, we have investigated the mechanism of cytotoxicity of STZ in insulin-secreting pancreatic cancer cells (Rin-5F) at different doses and time intervals. Cell viability, apoptosis, oxidative stress, and mitochondrial bioenergetics were studied. Our results showed that STZ induces alterations in glutathione homeostasis and inhibited the activities of the respiratory enzymes, resulting in inhibition of ATP synthesis. Apoptosis was observed in a dose- and time- dependent manner. Western blot analysis has also confirmed altered expression of oxidative stress markers (e.g., NOS and Nrf2), cell signaling kinases, apoptotic protein-like caspase-3, PARP, and mitochondrial specific proteins. These results suggest that STZ-induced cytotoxicity in pancreatic cells is mediated by an increase in oxidative stress, alterations in cellular metabolism, and mitochondrial dysfunction. This study may be significant in better understanding the mechanism of STZ-induced β-cell toxicity/resistance and the etiology of type 1 diabetes induction. 1. Introduction Streptozotocin (STZ), [N-(methylnitrosocarbamoyl)-α-D- glucosamine], is a broad spectrum antibiotic derived from the bacterium Streptomyces achromogenes [1]. It is a DNA alkylating agent and is often used as an antibacterial as well as anticancer agent [2, 3]. However, it is not a preferred drug for the treatment of cancers. This is due to genotoxic effects which lead to drug resistance [4]. STZ is known to be a pan- creatic beta-cell-specific cytotoxin and is therefore being widely used to induce experimental type 1 diabetes in rodent models [5, 6]. STZ is a glucose analogue that is selectively accumulated in pancreatic beta-cells via a GLUT 2 glucose transporter in the plasma membrane [7, 8]. STZ toxicity in beta-cells is dependent on GLUT 2 expression. Hosokawa and his col- leagues revealed that in transgenic mice, GLUT 2-expressing beta-cells are sensitive to the toxic effects of STZ whereas GLUT 1-expressing islets are completely resistant [9]. After entering the beta-cells via the GLUT 2 transporter, it causes DNA damage due to the DNA alkylating activity of its methyl nitrosourea moiety [10, 11], which, in turn, results in DNA fragmentation [12]. Subsequently, the fragmented DNA acti- vates poly (ADP-ribose) synthetase to repair DNA. Poly ADP-ribosylation leads to the depletion of cellular NAD+ and ATP [12, 13]. The decreased ATP synthesis is demon- strated by dephosphorylation which provides more sub- strates for xanthine oxidase, resulting in the formation of hydrogen peroxide and hydroxyl radicals [14, 15] causing oxidative stress. Furthermore, the presence of N-methyl-N- nitrosourea side chain has the ability to release nitric oxide [16, 17] that inhibits aconitase activity, resulting in mito- chondrial dysfunction. STZ is diabetogenic due to its targeted GLUT 2-dependent action in the pancreatic β-cells. The Hindawi Oxidative Medicine and Cellular Longevity Volume 2017, Article ID 7054272, 15 pages https://doi.org/10.1155/2017/7054272