Author(s)

Marwa E. Sayour¹, Rania M. Abd El Salam², Mohamed F. Elyamany², Abeer M. El Sayed³, Raafat A. El-Awady^1,4*

¹National Cancer Institute, Cairo University, Cairo, Egypt.
²Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
³Department of Pathology, National Cancer Institute, Cairo University, Cairo, Egypt.
⁴Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah, Sharjah, UAE.

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.

Paracetamol, Buthionine Sufoximine (BSO), Selective GSH Depletion, HepG2, Prostaglandin E2 (PGE2)

Sayour, M. , Abd El Salam, R. , Elyamany, M. , El Sayed, A. and El-Awady, R. (2016) Combination of Paracetamol and the Glutathione Depleting Agent Buthionine Sulfoximine Show Differential Effect on Liver Cancer Cells and Normal Hepatocytes. Pharmacology & Pharmacy, 7, 443-458. doi: 10.4236/pp.2016.711051.