Abstract 80: Streptozotocin-induced cytotoxicity and mitochondrial dysfunction in human hepatoma HepG2 cells

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Abstract Streptozotocin (STZ) is an antibiotic often used in the treatment of different types of cancers, including the liver cancer. STZ is also highly cytotoxic to the normal pancreatic beta-cells and therefore is being commonly used to develop experimental type 1 diabetes in rat and mouse models. Resistance towards STZ-induced cytotoxicity in cancer cells has also been reported. The precise molecular mechanism of STZ cytotoxicity/resistance in different tissues and carcinomas is, however unclear. STZ increases cellular oxidative stress by producing reactive oxygen (ROS) and nitrogen (RNS) species. We have investigated the mechanism of cytotoxicity of STZ in HepG2 cancer cells in culture. Cells were treated with different doses of STZ for different time intervals and the cytoxicity was studied by observing the alterations in oxidative stress, mitochondrial redox and respiratory functions. STZ induces ROS and RNS formation and oxidative stress as measured by an increase in the lipid peroxidation and nitrate production as well as alterations in the GSH metabolism. The mitochondria appear to be a more sensitive target for STZ toxicity than extramitochondrial compartments. The mitochondrial membrane potential was altered in STZ treated cells. Activities of the mitochondrial respiratory electron transporting enzymes; complex I and cytochrome c oxidase were also modulated resulting in the inhibition of ATP synthesis. The ROS-sensitive mitochondrial aconitase activity was also inhibited suggesting the involvement of oxidative stress in STZ-induced mitochondrial toxicity. The nuclear translocation of oxidative stress marker protein, NF-kB was increased in STZ treated cells. The expression of Hsp70, an oxidative stress marker protein, was also increased in the drug treated cells. The apparent absence of apoptotic markers such as cytochrome c release and the activation of caspase 3 in STZ treated HepG2 cells suggest that the intrinsic mitochondrial apoptosis pathway may not be primarily involved in STZ-induced cytotoxicity. The 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. This study may be significant in better understanding the mechanisms of STZ action in chemotherapy and drug resistance. The study is supported by Research Committee grant and a grant from Terry Fox Cancer Research funds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 80.