Streptozotocin-Induced Cytotoxicity, Oxidative Stress and Mitochondrial Dysfunction in Human Hepatoma HepG2 Cells

Abstract

Streptozotocin (STZ) is an antibiotic often used in the treatment of different types of cancers. It is also highly cytotoxic to the pancreatic beta-cells and therefore is commonly used to induce experimental type 1 diabetes in rodents. Resistance towards STZ-induced cytotoxicity in cancer cells has also been reported. Our previous studies have reported organ-specific toxicity and metabolic alterations in STZ-induced diabetic rats. STZ induces oxidative stress and metabolic complications. The precise molecular mechanism of STZ-induced toxicity in different tissues and carcinomas is, however, unclear. We have, therefore, investigated the mechanism of cytotoxicity of STZ in HepG2 hepatoma cells in culture. Cells were treated with different doses of STZ for various time intervals and the cytotoxicity was studied by observing the alterations in oxidative stress, mitochondrial redox and metabolic functions. STZ induced ROS and RNS formation and oxidative stress as measured by an increase in the lipid peroxidation as well as alterations in the GSH-dependent antioxidant metabolism. The mitochondria appear to be a highly sensitive target for STZ toxicity. The mitochondrial membrane potential and enzyme activities were altered in STZ treated cells resulting in the inhibition of ATP synthesis. ROS-sensitive mitochondrial aconitase activity was markedly inhibited suggesting increased oxidative stress in STZ-induced mitochondrial toxicity. These results suggest that STZ-induced cytotoxicity in HepG2 cells is mediated, at least in part, by the increase in ROS/RNS production, oxidative stress and mitochondrial dysfunction. Our study may be significant for better understanding the mechanisms of STZ action in chemotherapy and drug induced toxicity.

Streptozotocin Stimulates the Ion Channel TRPA1 Directly

“…Previous studies showed that decomposition of STZ leads to formation of both superoxide and nitric oxide (NO) (33)(34)(35). As these two react in a diffusion-controlled manner to form peroxynitrite (36), which is known to oxidize cysteines forming sulfenic acid and/or disulfides (37), we examined a direct reaction of STZ with cysteines.…”

“…Decomposition of STZ could lead to superoxide and finally H 2 O 2 (Scheme 1-i) (35,59), which is a two-electron oxidant known to activate TRPA1 channels (17). However, STZ decomposes to give both NO and superoxide (33)(34)(35)59), which are known to react in a diffusion-controlled manner to give peroxynitrite, a powerful oxidant that could produce all the cysteine modifications that we observed, i.e. cysteinyl radical, sulfenic acid, and disulfides (Scheme 1-ii) (37).…”

Short-Term Effects of Nose-Only Cigarette Smoke Exposure on Glutathione Redox Homeostasis, Cytochrome P450 1A1/2 and Respiratory Enzyme Activities in Mice Tissues

“…ROS in different tissues of control and CS-treated mice was measured using DCFDA as a fluorescent probe as described before [7,12,13,17]. …”

Hypoglycemic effect of catalpol on high-fat diet/streptozotocin-induced diabetic mice by increasing skeletal muscle mitochondrial biogenesis

“…Patients with insulin resistance or T2D also manifest decreased mitochondrial density, oxidative activity, and mitochondrial ATP synthesis [9,10]. A study on STZ-diabetic rats showed a persistent increase in reactive oxygen and nitrogen species (ROS and RNS, respectively) production and a decrease in the activities of the mitochondrial respiratory enzymes including ubiquinol-cytochrome c oxidoreductase (complex III) and cytochrome c oxidase (complex IV) [11]. Thus, increasing mitochondrial mass and oxidative activity is viewed as a potential therapeutic approach for the treatment of insulin resistance and diabetes, and minimizes the complications of diabetes or both [12].…”