{"title":"In-Vitro Antiproliferative Analysis of Metformin Hydrochloride on Androgen-Sensitive, LNCAP and Androgen-Insensitive, PC-3 Human Prostate Cancer Cell Lines","authors":"Brittney V. Hinton, Dolapo Adedeji, G. Payne","doi":"10.4236/PP.2017.83006","DOIUrl":"https://doi.org/10.4236/PP.2017.83006","url":null,"abstract":"Prostate cancer is one of the diseases worldwide that causes cancer-related deaths in men. Metformin is an antidiabetic drug that has been in use for over two decades for the treatment of Type II Diabetes mellitus (DM2). The purpose of this study was to evaluate the anti-proliferative property of metformin hydrochloride on androgen-sensitive, LNCAP and androgen-insensitive, PC-3 human prostate cancer cell lines at different concentrations (μM and mM) using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Metformin hydrochloride displayed a stronger cytotoxicity on the androgen-insensitive PC-3 than on the androgen-sensitive human prostate cancer cell lines. For both cell lines, the antiproliferative activity of metformin hydrochloride was best displayed at 0.1 mM concentration with average cell death percentage of 60% after 120-hour exposure.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"32 1","pages":"85-89"},"PeriodicalIF":0.0,"publicationDate":"2017-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88555956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Matsuda, M. Yoshikawa, Takugi Kan, Mariko Watanabe, J. Ajimi, Shigeru Takahashi, M. Miura, Kenji Ito, Hiroyuki Kobayashi, Toshiyasu Suzuki
{"title":"Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level","authors":"M. Matsuda, M. Yoshikawa, Takugi Kan, Mariko Watanabe, J. Ajimi, Shigeru Takahashi, M. Miura, Kenji Ito, Hiroyuki Kobayashi, Toshiyasu Suzuki","doi":"10.4236/PP.2017.82003","DOIUrl":"https://doi.org/10.4236/PP.2017.82003","url":null,"abstract":"Our group has earlier demonstrated that three enzymes sensitive to peptidase inhibitors (PIs), amastatin (A)-, captopril (C)-, and phosphoramidon (P), played an important role in inactivation of enkephalins at the spinal level. Dynorphin-converting enzyme (DCE) hydrolyzes dynorphin (Dyn) A (1-17) or Dyn A (1-13) mainly at the Arg6-Arg7 bond. Dynorphin A and its derived peptides interact with opioid and glutamate receptors at their N- and C-terminals, respectively. The purpose of the present study was to evaluate the antinociceptive potency and toxicity of intrathecal administered Dyn A (1-17), Dyn A (1-13), or Dyn A (1-6) under pretreatment with ACP and/or the DCE inhibitor p-hydroxymercuribenzoate (PHMB). The effect of these PIs on Dyn A (1-17)-induced inhibition of electrically-evoked contractions in mouse vas deferens was also investigated. The inhibitory potency of Dyn A (1-17) on electrically-evoked contractions in mouse vas deferens under pretreatment with ACP was higher than that with AC, AP, or CP. Pretreatment with ACP augmented Dyn A (1-17) or (1-13)-induced antinociception by approximately 50- or 30-fold with no sign of allodynia when administered intrathecally at low doses. Pretreatment with ACP and PHMB induced neuropathy. These findings showed that intrathecal administration of low-dose Dyn A (1-17) or DynA (1-13) increased antinociception under pretreatment with ACP, but without signs of allodynia in rat.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"116 1","pages":"33-51"},"PeriodicalIF":0.0,"publicationDate":"2017-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79171759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdullah Al Mamun, M. Hossain, M. Uddin, Md. Tanjir Islam, Sajjad Hossain, M. Hossain, Md. Farhad Hossain, Ataur Rahman Sujan, M. Rashid, Md. Mahbubur Rahman, A. F. M. Towheedur Rahman
{"title":"Comparison of the Hypoglycemic, Hypolipidemic and Hepatoprotective Effects of Asparagus racemosus Linn. in Combination with Gliclazide and Pioglitazone on Alloxan-Induced Diabetic Rats","authors":"Abdullah Al Mamun, M. Hossain, M. Uddin, Md. Tanjir Islam, Sajjad Hossain, M. Hossain, Md. Farhad Hossain, Ataur Rahman Sujan, M. Rashid, Md. Mahbubur Rahman, A. F. M. Towheedur Rahman","doi":"10.4236/PP.2017.82004","DOIUrl":"https://doi.org/10.4236/PP.2017.82004","url":null,"abstract":"In recent years, the popularity of medicinal plants as a remedy has been increased manifold due to having minimal adverse effects. The current study aimed to compare the hypoglycemic, hypolipidemic and hepatoprotective effects of the ethanolic extract of Asparagus racemosus (EEAR) Linn. alone and combinedly with conventional antidiabetic agents (gliclazide and pioglitazone) in alloxan-induced diabetic rats. Diabetes was induced in male Wister albino rats by the administration of single intra-peritoneal injection of alloxan monohydrate (120 mg/kg b.w.). Effect of oral administration of two different doses of EEAR (200 and 400 mg/kg b.w.), gliclazide (10 mg/kg b.w.) and pioglitazone (10 mg/70kg/b.w.) alone for 2 weeks and a combination of EEAR (200 mg/kg b.w.) with either gliclazide (10 mg/kg b.w.) or pioglitazone (10 mg/70kg/b.w.) for 2 weeks were examined on hypoglycemic activity on 0th, 5th, 10th and 14th day of treatment. After 2 weeks of treatment, hypolipidemic and hepatoprotective effects were estimated by serum biochemical markers such as total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), very low density lipoprotein (VLDL), high density lipoprotein (HDL), serum glutamate oxaloacetate transaminases (SGOT), serum glutamate pyruvate trans-aminases (SGPT) and total protein (TP) with the help of commercially available kits. The survival rate, body weight and organ weight were also measured. Alloxan treatment resulted in persistent hyperglycemia, hyperlipidemia and liver dysfunction in rats. Treatment with EEAR at different doses improved hyperglycemia significantly (p < 0.05, p < 0.01, p < 0.001; p < 0.05, p < 0.01; p < 0.05) by reducing the blood glucose levels in rats on 10th and 14th day of treatment in a dose-dependent mood when compared to the disease control rats, gliclazide treated rats and pioglitazone treated rats. The combination therapy significantly (p < 0.001; p < 0.01, p < 0.001; p < 0.05, p < 0.01, p < 0.001) promoted the glucose-lowering activity on 5th, 10th and 14th day of treatment as compared to that of disease control rats, gliclazide treated rats and pioglitazone treated rats. Proposed adjunct therapy also markedly (p < 0.001; p < 0.01, p < 0.001) improved serum TG, HDL and LDL level with insignificant change in VLDL and TC level while comparing with groups receiving gliclazide treated rats and pioglitazone treated rats. Administration of different doses of EEAR markedly (p < 0.05, p < 0.01, p < 0.001; p < 0.05, p < 0.01; p < 0.05) reduced the activity of TC, TG, LDL, VLDL and HDL cholesterol levels in a dose-dependent approach with respect to that of gliclazide treated rats and pioglitazone treated rats. The effect of combination therapy significantly (p < 0.001; p < 0.001; p < 0.01, p < 0.001) decreased the SGOT, SGPT and TP hepatic enzyme levels when compared to disease control rats, gliclazide treated rats and pioglitazone treated rats indicated improvement in liver dysfunctions. Administration o","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"55 2 1","pages":"52-74"},"PeriodicalIF":0.0,"publicationDate":"2017-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77466258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Bhatt, G. Singh, Sanjeev Kumar, Rachna Paliwal, J. S. Jangwan, C. P. Singh
{"title":"Synthesis and Biological Activity Study of Novel N1-(4-Hydroxy Benzoyl)-3-Methyl-5-Phenyl-4(N-4-Chlorophenylazo)-1,2-Diazole and Its Derivatives","authors":"S. Bhatt, G. Singh, Sanjeev Kumar, Rachna Paliwal, J. S. Jangwan, C. P. Singh","doi":"10.4236/PP.2017.81001","DOIUrl":"https://doi.org/10.4236/PP.2017.81001","url":null,"abstract":"A series of sulpha/substituted derivatives of phenyl azo-1,2-diazole have been synthesized and tested as an anti-inflammatory and anti-bacterial activity in mature albino rats hind paw by taking Diclofenac sodium as standard. N1-(4-hydroxy benzoyl)-3-methyl-5-phenyl-4(N-4-chlorophenylazo)-1,2-diazole is synthesized by a two-step process. In the first step, synthesis of N1-4-chlorophenyl hydrazono-1-methyl-3-phenyl propane-1,3-dione by the reciprocal action of 1-methyl-5-phenylpropane-1,3-dione and diazonium salt solution of phenyl-chloride interacts with 4-hydroxybenzoic acid hydrazide to form the final compound. These diazoles, the heterocyclic compounds which contained electron withdrawing groups, were screened for analgesic activity by acetic acid induced writing method, and for anti-inflammatory activity carried on carrageenan-induced paw edema. The synthesized substituted Chlorophenylazo-1,2-diazole nucleus exhibited significant anti-bacterial, anti-cancer, anti-inflammatory activity, muscle relaxing and moderate activity in anti-proliferative studies.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"24 1","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2017-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78143051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cheng‐Hsin Yen, A. Mohammad, M. Schneider, S. Poole, B. Lowry, Brenda W. Mc Curdy, P. Faustino, Saeed R. Khan
{"title":"Development and Application of a Validated UHPLC Method for the Determination of Atropine and Its Major Impurities in Antidote Treatment Nerve Agent Auto-Injectors (ATNAA) Stored in the Strategic National Stockpiles","authors":"Cheng‐Hsin Yen, A. Mohammad, M. Schneider, S. Poole, B. Lowry, Brenda W. Mc Curdy, P. Faustino, Saeed R. Khan","doi":"10.4236/PP.2017.81002","DOIUrl":"https://doi.org/10.4236/PP.2017.81002","url":null,"abstract":"The development and implementation of advanced analytical technologies is essential for extending the expiry for complex drug products stored in the Strategic National Stockpiles. Consequently, a novel Ultra High-Performance Liquid Chromatographic (UHPLC) method has been developed for the analysis of atropine and its respective impurities to support the analytical research platform for auto-injectors. This study is part of a larger research effort to improve the efficiency and broaden the applicability of advanced analytical methods for medical counter-measure medications. The current HPLC compendial methodology for atropine sulfate injection requires an analysis time of 40 minutes for atropine. In comparison, the novel gradient UHPLC method required only 8 minutes to evaluate both atropine and its major pharmaceutical impurities. Improved separation was achieved on a Waters Acquity UHPLC BEH C18 1.7 μm, 2.1 × 100 mm column employing gradient elution of mobile phase solvent A (0.1% H3PO4) and solvent B (0.1% H3PO4, 90% ACN, and 10% H2O). The method was validated according to USP Category I requirements for assay. The daily standard calibration curves were linear over a concentration range from 50 μg/mL to 250 μg/mL with a correlation coefficient of >0.999. The detection limit (LOD) and quantitation limit (LOQ) were 3.9 μg/ml and 13.1 μg/ml, respectively. Resolution results indicate that atropine and the following impurities, degradants and a preservative can also be separated and analyzed using this proposed method: noratropine, 4,4’-di-hy-droxydiphenyl ether, 2,4’-dihydroxydiphenyl ether, 4-bromophenol, 4-hydro-xyatropine, tropic acid, apoatropine HCl, atropic acid, hydroquinone, nitroethane, phenol and catechol. The UHPLC method demonstrated enhanced selectivity and significantly reduced the analysis time when compared with the traditional USP compendial HPLC method. The method was successfully applied to the evaluation of atropine in ATNAA auto-injectors lots from the Strategic National Stockpiles.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"140 1","pages":"15-31"},"PeriodicalIF":0.0,"publicationDate":"2017-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77552406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Up-Regulation of Local TGF-β Contributes to a Decrease in Renal Tubular Na + -K + ATPase and Hyperkalemia in a Mouse Model of Crush Syndrome","authors":"S. Mizuno, Y. Mizuno-Horikawa","doi":"10.4236/PP.2016.712054","DOIUrl":"https://doi.org/10.4236/PP.2016.712054","url":null,"abstract":"Hyperkalemia is one of the most important risk factors in patients suffering from crush syndrome with rhabdomyolysis. Glycerol-injected animals have been used as an experimental model of rhabdomyolysis-induced acute kidney injury (AKI), but little information is available for the onset and molecular mechanism of hyperkalemia. In our murine model, plasma potassium levels increased after a single injection of 50%-glycerol solution (10 ml/kg, i.m.) during the progression of muscular and renal injuries. Renal tubular Na+-K+-ATPase functions as ion-exchange pomp for potassium clearance from blood into renal tubular epithelial cells. Renal histochemistry revealed an apparent decrease in the tubular Na+-K+-ATPase expression, especially at 24 hours post-glycerol challenge in our AKI model. In contrast to the loss in active Na+-K+-ATPase, there was a significant increase in the renal levels of transforming growth factor-β (TGF-β) that is known to suppress Na+-K+-ATPase production in vitro. When anti-TGF-β antibody was administered in mice after the glycerol challenge, the suppression of renal Na+-K+-ATPase activity was partially restored. As a result, hyperkalemia was improved in the TGF-β-neutralized AKI mice, associated with a significant decrease in plasma potassium concentration. Taken together, we predict that endogenous TGF-β is a key regulator for inhibiting Na+-K+-ATPase production and, in part, enhancing hyperkalemia during progression of rhabdomyolysis-induced AKI. This is, to our knowledge, the first report to determine a critical role of endogenous TGF-β in renal potassium metabolism during crush syndrome.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"2 1","pages":"481-492"},"PeriodicalIF":0.0,"publicationDate":"2016-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75655111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Fluconazole Prophylaxis in Neonates (Non-Systematic) Literature Review","authors":"A. Almulhim","doi":"10.4236/PP.2016.712053","DOIUrl":"https://doi.org/10.4236/PP.2016.712053","url":null,"abstract":"Background: Nosocomial infection remains an important contributing factor for morbidity and mortality in neonates. Coagulase-negative staphylococci have emerged as the predominant pathogens of late onset sepsis. This is followed by staphylococcus aurous, gram negative bacilli, and fungi. Old studies noted that mortality due to candidemia was higher in infants weigh less than 2000 g after being exposed to risk factors. The prophylactic use of fluconazole for the prevention of IC in extremely low birth weight was first reported in 2001. Methods: Current guidelines from Europe and North America that refer to the treatment of fungal infections are included. Literature search was performed using Medline, Scopus and Cochrane Central Register of Controlled Trials through March, 2016. Conclusion: Mortality was not different in early studies. However, recent studies concluded that mortality was reduced in the fluconazole arms. Risk-based approach towards fluconazole prophylaxis seems to be safe and effective.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"29 1","pages":"473-480"},"PeriodicalIF":0.0,"publicationDate":"2016-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83084018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yoshiaki Kimura, Koki Muryoi, Mika Shibata, N. Ozaki, K. Arai
{"title":"In Vivo Interaction of Morphine and Diclofenac","authors":"Yoshiaki Kimura, Koki Muryoi, Mika Shibata, N. Ozaki, K. Arai","doi":"10.4236/PP.2016.712055","DOIUrl":"https://doi.org/10.4236/PP.2016.712055","url":null,"abstract":"The number of studies on possible pharmacokinetic interactions between opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used in combination for the treatment of chronic pain, is limited. In rats, the major metabolic pathway of morphine is glucuronidation to morphine-3-glucuronide (M3G) by UDP-glucuronosyltransferase. In this study, we investigated the influence of diclofenac (NSAID) on the formation of M3G in vitro using rat liver tissue homogenates. Competitive inhibition of M3G formation by diclofenac was observed with an average Ki of 19.9 μM. Because these in vitro findings suggested that a pharmacokinetic interaction occurs in vitro , we investigated whether diclofenac inhibits the glucuronidation of morphine in rats. A single dose of diclofenac increased serum concentrations of both morphine and M3G and showed a higher analgesic efficacy in the Von Frey test. Furthermore, diclofenac caused a net decrease in morphine urine concentrations, but the excretion of M3G through biliary and urinary routes was unchanged. These results demonstrated that in contrast to in vitro data a single dose of diclofenac did not alter the glucuronidation of morphine in vitro .","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"1 1","pages":"493-503"},"PeriodicalIF":0.0,"publicationDate":"2016-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74000117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Hasan, Ghazaleh Farghadani, Salaa Khalid AlHaideri, Mohamed Fathy
{"title":"Pharmacist Opportunities to Improve Public Self-Medicating Practices in the UAE","authors":"S. Hasan, Ghazaleh Farghadani, Salaa Khalid AlHaideri, Mohamed Fathy","doi":"10.4236/PP.2016.711052","DOIUrl":"https://doi.org/10.4236/PP.2016.711052","url":null,"abstract":"Objective: Self-treatment is an important aspect of self-care and one of the vital issues under debate in health care. Self-medication patterns vary among different populations and are influenced by many factors. The objective was to investigate the nature of self-medication behavior among the general public in the UAE and to explore public attitudes, beliefs, and level of knowledge concerning self-medication. Methods: A purposive sample of individuals involved in self-medication who belong to different age, gender, income, education level and health-seeking behaviors. A qualitative approach through individual face-to-face interviews was utilized to investigate participants’ behaviors and attitudes towards self-medication; factors influencing decision to self medicate, sources of information on medications, types of conditions for which self-medication is sought and types of medications used. Participant recruitment continued until theme saturation using content analysis. Findings: Three themes emerged from the data: Reasons for self-medication such as costs associated with visiting a doctor, convenience in visiting a pharmacy and perception of simplicity of the condition; Sources of information: pharmacists as a main source in addition to medication leaflets, family role and previous use, and medicines and medicines’ use: medicines’ use in chronic disease, use of antibiotics, use of herbals and supplements and medicines’ use in children. Conclusion: Findings from this study indicate that self-medication behaviors are common among the population due to several reasons. Inappropriate self-medication practices are evident and may compromise patient care outcomes. Pharmacists play a vital role in intervening to optimize the use of medications and patient education regarding self-care.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"61 1","pages":"459-471"},"PeriodicalIF":0.0,"publicationDate":"2016-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73088690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marwa E. Sayour, R. M. A. Salam, Mohamed F. El-yamany, A. Sayed, R. El-Awady
{"title":"Combination of Paracetamol and the Glutathione Depleting Agent Buthionine Sulfoximine Show Differential Effect on Liver Cancer Cells and Normal Hepatocytes","authors":"Marwa E. Sayour, R. M. A. Salam, Mohamed F. El-yamany, A. Sayed, R. El-Awady","doi":"10.4236/PP.2016.711051","DOIUrl":"https://doi.org/10.4236/PP.2016.711051","url":null,"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.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":"19 2 1","pages":"443-458"},"PeriodicalIF":0.0,"publicationDate":"2016-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83333421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}