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

作     者：Marwa E. Sayour Rania M. Abd El Salam Mohamed F. Elyamany Abeer M. El Sayed Raafat A. El-Awady Marwa E. Sayour;Rania M. Abd El Salam;Mohamed F. Elyamany;Abeer M. El Sayed;Raafat A. El-Awady

作者机构：National Cancer Institute Cairo University Cairo Egypt Department of Pharmacology & Toxicology Faculty of Pharmacy Cairo University Cairo Egypt Department of Pathology National Cancer Institute Cairo University Cairo Egypt Sharjah Institute for Medical Research and College of Pharmacy University of Sharjah Sharjah UAE 

出 版 物：《Pharmacology & Pharmacy》 (药理与制药（英文）)

年 卷 期：2016年第7卷第11期

页      面：443-458页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Paracetamol Buthionine Sufoximine (BSO) Selective GSH Depletion HepG2 Prostaglandin E2 (PGE2) 

摘      要：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.