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| 1 | Preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma显示文摘AIM: To evaluate the efficacy and the safety of azathioprine (AZA) and buthionine sulfoximine (BSO) bylocalized application into HepG2 tumor in vivo.METHODS: Different hepatoma and colon carcinoma cell lines (HepG2, HuH7, Chang liver, LoVo, RKO, SW-48, SW-480) were grown in minimal essencial medium supplemented with 10% fetal bovine serum and 1% antibiotic/antimycotic solution and maintained in a humidified 37 ℃ incubator with 5% CO2. These cells were pretreated with BSO for 24 h and then with AZA for different times. We examined the effects of this combination on some proteins and on cellular death. We also studied the eff icacy and the safety of AZA (6 mg/kg per day) and BSO (90 mg/kg per day) in HepG2 tumor growth in vivo using athymic mice. We measured safety by serological markers such as aminotransferases and creatine kinase.RESULTS: The in vitro studies revealed a new mechanism of action for the AZA plus BSO combination in the cancer cells compared with other thiopurines (6-mercaptopurine, 6-methylmercaptopurine, 6-thioguanine and 6-methylthioguanine) in combination with BSO. The cytotoxic effect of AZA plus BSO in HepG2 cells resulted from necroptosis induction in a mitochondrial-dependent manner. From kinetic studies we suggest that glutathione (GSH) depletion stimulates c-Jun amino-terminal kinase and Bax translocation in HepG2 cells with subsequent deregulation of mitochondria (cytochrome c release, loss of membrane potential), and proteolysis activation leading to loss of membrane integrity, release of lactate dehydrogenase and DNA degradation. Some of this biochemical and cellular changes could be reversed by N-acetylcysteine (a GSH replenisher). In vivo studies showed that HepG2 tumor growth was inhibited when AZA was combined with BSO.CONCLUSION: Our studies suggest that a combination of AZA plus BSO could be useful for localizedtreatment of hepatocellular carcinoma as in the currently used transarterial chemoembolization method. | Borja Hernández-Breijo Jorge Monserrat Sara Ramírez-Rubio Eva P Cuevas Diana Vara Inés Díaz-Laviada M Dolores Fernández-Moreno Irene D Román Javier P Gisbert Luis G Guijarro | 2011 | World Journal of Gastroenterology2011，17，34： | 2 |
| 2 | Texturometer as a tool for studying varietal differences in wheat flour doughs and gluten proteins显示文摘 | Ram B P Nigam S N | 1983 | J Texture Stud1983，14，： | 1 |
| 3 | Surface water of a perennial river exhibits multi-antimicrobial resistant shiga toxin and enterotoxin producing Escherichia coli显示文摘 | Ram S Vajpayee P Singh R L | 2009 | Ecotoxicology and Environmental Safety2009，72，2： | 1 |
| 4 | Anhydrous ethanol: A renewable source of energy显示文摘 | SANTOSH K NEETU S RAM P | 2010 | Renew Sust Energ Rev2010，14，： | 1 |
| 5 | Survival of solenopsis mealybug, Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae) on cotton in relationto abotic and biotic factors显示文摘 | Kedar S C Saini R K Ram P | 2012 | International Journal of Plant Protection2012，5，2： | 1 |
| 6 | Production of fructooligosacchar- ides from inulin by endoinulinases and their prebiotic po- tential 显示文摘 | Ram S S Rupinder P S | 2010 | Food Technology and Biotechnology2010，48，4： | 1 |
| 7 | Expression profiling of various genes during the fruit development and ripening of mango显示文摘 | Sagar S P Ram S K Ashok P G | 2010 | Plant Physiol Biochem2010，48，6： | 1 |
| 8 | The role of porins in neisserial pathogenesis and immunity显示文摘 | Massari P Ram S Macleod H | 2003 | Trends Mierobiol2003，11，2： | 1 |
| 9 | A comparison of modeling and imaginary in the acqui- sition and retention of motor skills 显示文摘 | Ram N Riggs S M Landers D M McCullagh P | 2007 | Journal of Sports Sciences2007，25，5： | 1 |
| 10 | Influence of dietary HUFA levels on reproductive performance, tissue fatty acid profile and desaturase and elongase mRNAs expression in female zebrafish( Danio rerio) 显示文摘 | Jaya - Ram A Kuah M K Lim P S | 2008 | Aquaculture2008，277，： | 1 |
| 11 | Triglycerides-based Diesel Fuels显示文摘 | Anjana S Ram P | 2000 | Renewable and Sustainable Energy Reviews2000，4，2： | 1 |
| 12 | Solvent retention capacities of Indian wheats and their relationship with biscuit making quality显示文摘 | Ram S Singh R P | 2004 | Cereal Chemistry2004，81，： | 1 |
| 13 | Artificial recharge in multiaquifers of a mountainous watershed显示文摘 | MAJUMDAR P K RAM S RAO P R | 2009 | Journal of Hydrologic Engineering2009，14，3： | 1 |
| 14 | Inhibition of CO2 Corrosion of Mild Steel by Inidazoline Corrosion Inhibitor 显示文摘 | JOVANCICEVIC V RAM ACHANDRAN S PRINCE P | 1998 | Corro- sion1998，3，6： | 1 |
| 15 | Triglycerides-based diesel fuel 显示文摘 | ANJANA S RAM P | 2000 | Renewable and Sustainable Energy Reviews2000，4，2： | 1 |
| 16 | Synthesis and cha racterization o{ ammonium molybdophosphatesilica nano- composite (AMP Si()2 ) as a prospective sorbent {or the se- paration of ':7Cs from nuclear waste显示文摘 | Ingale S V Ram R Sastry P U | | J Radioanal Nucl Chem 201 10，301，： | 1 |
| 17 | Seasonal shift in net ecosystem production in a tropical estuary显示文摘 | Ram A S P Nair S Chandramohan D | 2003 | Limnology and Oceanography2003，48，： | 1 |
| 18 | G protein pathways 显示文摘 | Neves S R Ram P T Iyengar R | 2002 | Sci- ence2002，296，： | 1 |
| 19 | Effects of cooling and freezing storage on the stability of bioactive factors in human colostrum显示文摘 | Ramírez S C Pérez-Cano F J Audí C | | 0，，05： | 1 |
| 20 | Enterococci in river Ganga surface waters: propensity of species distribution, dissemination of antimicrobial-resistance and virulence-markers among species along landscape显示文摘 | Lata P Ram S Agrawal M | 2009 | BMC Microbiology2009，9，： | 1 |
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