Abstract
Abstract Bacterial lipopolysaccharides (LPS) induce cytotoxicity in vitro and inflammation-induced toxic responses in vivo. Use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, has been reported to be beneficial in inflammation-associated diseases like cancer and diabetes. Their precise molecular mechanisms, however, are not clearly understood. Our previous studies on aspirin treated HepG2 cells strongly suggest cell cycle arrest and induction of apoptosis associated with mitochondrial dysfunction. In the present study, we have further demonstrated that HepG2 cells treated with LPS alone or in combination with aspirin induces subcellular toxic responses which are accompanied by increase in reactive oxygen species (ROS) production, oxidative stress, apoptosis and mitochondrial respiratory dysfunction. The LPS/Aspirin induced toxicity was attenuated by pretreatment of cells with N-acetyl cysteine (NAC). Oxidative stress and glutathione-dependent redox-homeostasis in the mitochondria were altered more severely compared to the extramitochondrial compartment of cells. Pre-treatment of HepG2 cells with NAC has demonstrated selective protection in redox homeostasis and mitochondrial dysfunction. Our results suggest that altered glutathione (GSH)-redox metabolism, oxidative stress and mitochondrial function in HepG2 cells play a critical role in LPS/aspirin-induced cytotoxicity. These results may help in better understanding the pharmacological and toxicological properties of NSAIDs in cancer cells exposed to bacterial endotoxins. (Supported by Sheikh Hamdan Medical Research Grant and Terry Fox Cancer Research Funds and a fund from CMHS Research Committee). Citation Format: Haider Raza, Annie John, Jasmin shafarin. Potentiation of LPS-induced toxicity in human hepatoma HepG2 cells by aspirin and its protection by N-acetyl cysteine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3057. doi:10.1158/1538-7445.AM2015-3057
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