Combination of Paracetamol and the Glutathione Depleting Agent Buthionine Sulfoximine Show Differential Effect on Liver Cancer Cells and Normal Hepatocytes

Marwa E. Sayour, R. M. A. Salam, Mohamed F. El-yamany, A. Sayed, R. El-Awady
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引用次数: 2

Abstract

Background: Paracetamol exerts toxic effects on liver cells through its metabolism into N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by conjugation with cellular glutathione (GSH). Once GSH is depleted, NAPQI stimulates a range of oxidative reactions that result in cell necrosis. The aim of the present investigation is to find a new strategy that would selectively protect normal hepatic tissues and sensitize liver cancer cells to the toxic effects of paracetamol or its metabolite. This may lead to the development of a targeted therapy for liver cancer. Methods: The anti-proliferative effects of paracetamol and buthionine sulfoximine BSO (a glutathione depleting agent) alone and in combination on the liver cancer cells HepG2 and normal rat hepatocytes were investigated by sulphorhodamine-B assay. Effects on cell cycle regulation and induction of apoptosis were tested by flow cytometry. The level of prostaglandin expression was measured by ELISA. Results: The present study showed that both agents alone or in combination have anti-proliferative effects on both cell types. Surprisingly, BSO showed a cytoprotective effects on normal hepatocytes treated with high concentrations (1.75 and 2 mM) of paracetamol. This was confirmed by cell cycle analysis that recorded decreased fraction of sub-G1 cells indicating reduction of apoptosis in normal hepatocytes. Analysis of prostaglandin E2 revealed differential effects of paracetamol on normal and liver cancer cells. A significant increase in PGE2 level over the control was observed in normal hepatocytes whereas a significant decrease was seen in HepG2 cells after treatment with paracetamol. Conclusion: These results indicate that combination of paracetamol/BSO has differential effects on liver cancer cells and normal hepatocytes, which opens the avenue for a new effective and selective combination for management of liver cancer.
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对乙酰氨基酚和谷胱甘肽消耗剂丁硫氨酸亚砜对肝癌细胞和正常肝细胞的不同作用
背景:扑热息痛通过代谢为n -乙酰基-对苯醌亚胺(NAPQI)对肝细胞产生毒性作用,NAPQI通过与细胞谷胱甘肽(GSH)结合解毒。一旦谷胱甘肽被耗尽,NAPQI刺激一系列氧化反应,导致细胞坏死。本研究的目的是寻找一种新的策略,可以选择性地保护正常肝组织,并使肝癌细胞对扑热息痛或其代谢物的毒性作用敏感。这可能会导致肝癌靶向治疗的发展。方法:采用硫代丹- b法观察对乙酰氨基酚和丁硫胺亚砜BSO(一种谷胱甘肽消耗剂)单用和联用对肝癌细胞HepG2和正常大鼠肝细胞的抗增殖作用。流式细胞术检测其对细胞周期调节和诱导凋亡的影响。ELISA法检测前列腺素表达水平。结果:本研究表明,这两种药物单独或联合使用对两种细胞类型都有抗增殖作用。令人惊讶的是,BSO对高浓度(1.75 mM和2 mM)扑热息痛处理的正常肝细胞显示出细胞保护作用。细胞周期分析证实了这一点,记录的亚g1细胞比例减少表明正常肝细胞凋亡减少。前列腺素E2分析显示对乙酰氨基酚对正常和肝癌细胞的不同影响。在正常肝细胞中,PGE2水平显著高于对照组,而在使用扑热息痛治疗后,HepG2细胞的PGE2水平显著降低。结论:对乙酰氨基酚/BSO联合用药对肝癌细胞和正常肝细胞有不同的影响,为肝癌治疗开辟了一种新的有效、选择性的联合用药途径。
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