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Com.ination of.Paracetam.l and the Glutathione Depleting Agent Buthionine Sulf.xim.ne Show Dif.erential Ef.ect on Liver Cancer Cells and Norm.l Hepatocytes

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Pharm.cology & Pharm.cy 2016年第11期7卷 443-458页

作者： m.rwa E. Sayour rania m. abd el salam.mohamed f. elyamany Abeer m. el Sayed Raaf.t A. el-Awady National Cancer Institute Cairo University Cairo Egypt Departm.nt of.Pharm.cology & Toxicology Faculty of Pharmacy Cairo University Cairo Egypt Departm.nt of.Pathology National Cancer Institute Cairo University Cairo Egypt Sharjah Institute f.r m.dical Research and College of.Pharm.cy University of Sharjah Sharjah UAE

Background: Paracetam.l exerts toxic ef.ects on liver cells through its m.tabolism.into N-acetyl-p-benzoquinone im.ne (NAPQI), which is detoxif.ed by conjugation with cellular glutathione (GSH). Once GSH is depleted, NAPQI stim.lates a range of.oxidative reactions that result in cell necrosis. The aim.of.the present investigation is to f.nd a new strategy that would selectively protect norm.l hepatic tissues and sensitize liver cancer cells to the toxic ef.ects of.paracetam.l or its m.tabolite. This m.y lead to the developm.nt of.a targeted therapy f.r liver cancer. m.thods: The anti-prolif.rative ef.ects of.paracetam.l and buthionine sulf.xim.ne BSO (a glutathione depleting agent) alone and in com.ination on the liver cancer cells HepG2 and norm.l rat hepatocytes were investigated by sulphorhodam.ne-B assay. Ef.ects on cell cycle regulation and induction of.apoptosis were tested by f.ow cytom.try. The level of.prostaglandin expression was m.asured by elISA. Results: The present study showed that both agents alone or in com.ination have anti-prolif.rative ef.ects on both cell types. Surprisingly, BSO showed a cytoprotective ef.ects on norm.l hepatocytes treated with high concentrations (1.75 and 2 m.) of.paracetam.l. This was conf.rm.d by cell cycle analysis that recorded decreased f.action of.sub-G1 cells indicating reduction of.apoptosis in norm.l hepatocytes. Analysis of.prostaglandin E2 revealed dif.erential ef.ects of.paracetam.l on norm.l and liver cancer cells. A signif.cant increase in PGE2 level over the control was observed in norm.l hepatocytes whereas a signif.cant decrease was seen in HepG2 cells af.er treatm.nt with paracetam.l. Conclusion: These results indicate that com.ination of.paracetam.l/BSO has dif.erential ef.ects on liver cancer cells and norm.l hepatocytes, which opens the avenue f.r a new ef.ective and selective com.ination f.r m.nagem.nt of.liver cancer.

关键词： Paracetam.l Buthionine Suf.xim.ne (BSO) Selective GSH Depletion HepG2 Prostaglandin E2 (PGE2)

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