Streptozotocin-induced cytotoxicity, oxidative stress and mitochondrial dysfunction in human hepatoma HepG2 cells.
Streptozotocin-induced cytotoxicity, oxidative stress and mitochondrial dysfunction in human hepatoma HepG2 cells.
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DOI：
10.3390/ijms13055751
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发表时间：
2012
影响因子：
5.6
通讯作者：
John A
中科院分区：
文献类型：
--
作者：
Raza H;John A
链脲佐菌素（STZ）是一种抗生素，常用于治疗不同类型的癌症。它对胰腺β细胞也具有高度细胞毒性，因此常用于在啮齿动物中诱导实验性1型糖尿病。还报道了癌细胞对STZ诱导的细胞毒性的抵抗力。我们先前的研究报告了STZ诱导的糖尿病大鼠的器官特异性毒性和代谢改变。STZ诱导氧化应激和代谢并发症。然而，STZ在不同组织和肿瘤中诱导毒性的确切分子机制尚不清楚。因此，我们研究了STZ在培养的HepG 2肝癌细胞中的细胞毒性机制。用不同剂量的STZ处理细胞不同的时间间隔，通过观察氧化应激，线粒体氧化还原和代谢功能的变化来研究细胞毒性。STZ诱导ROS和RNS的形成和氧化应激的脂质过氧化反应的增加，以及GSH依赖的抗氧化剂代谢的改变测量。线粒体似乎是STZ毒性的高度敏感的靶标。STZ处理细胞后，线粒体膜电位和酶活性发生改变，ATP合成受到抑制。ROS敏感的线粒体顺乌头酸酶活性被显著抑制，表明STZ诱导的线粒体毒性中的氧化应激增加。这些结果表明，STZ诱导的细胞毒性在HepG 2细胞介导的，至少部分，在ROS/RNS生产，氧化应激和线粒体功能障碍的增加。本研究对进一步了解STZ在化疗中的作用机制和药物毒性有重要意义。
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.
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DOI：
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发表时间：
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影响因子：
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