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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 | Microstructure and tensile properties of Inconel 718 pulsed Nd-YAG laser welds 显示文摘 | JANAKI RAM G D VENUGOPAL A PRASAD K | 2005 | Journal of Material Processing Technology2005，167，： | 1 |
| 3 | Salinity andsodicity effects on respiration and microbial biomass of soil 显示文摘 | VANESSA N L W RAM C D RICHARD S B G | 2008 | Biology and Fertility of Soils2008，44，： | 1 |
| 4 | Microstructural evolution during friction surfacing of tool steelH13显示文摘 | Khalid Rafi H Janaki Ram G D Phanikumar G | 2011 | Materials & Design2011，32，： | 1 |
| 5 | Use of ultrasonic consolidation forfabrication of multi-material strurtures显示文摘 | JANAKI RAM G D ROBINSON C YANG Y | 2007 | RapidPrototyping Journal2007，13，： | 1 |
| 6 | Parallel Simulated Annealing Algorithms 显示文摘 | Ram D J Sreenivas T Subramaniam K G | 1996 | Journal of Parallel and Distributed Computing (S0743 -7315)1996，37，2： | 1 |
| 7 | Optimum conditions for in vitro chicken IL-2 production an castle disease vaccinated chickens显示文摘 | Thiagarajan D Ram G C Bansal M P | 1999 | Vet Immunol Immuno pathol1999，67，1： | 1 |
| 8 | Microstructure and tensile properties of Inconel 718 pulsed Nd-YAG laser welds显示文摘 | Janaki Ram G D Venugopal A Prasad K | 2005 | Journal of Material Processing Techology2005，167，： | 1 |
| 9 | Use of inoculants to refine weld solidification structure and improve weldablilty in type 2090A1 - Li alloy 显示文摘 | RAM G D MITRA T K J RAJU M K | 2000 | Materials Science and Engineering A2000，276，1： | 1 |
| 10 | Isolation and charac- terization of Ustilaginoideavirens and survey of false smut disease of rice in India显示文摘 | Ladhalakshmi D Laha G S Singh Ram | 2012 | Phytoparasitica2012，40，2： | 1 |
| 11 | Microstructural refine- ment through inoculation of type 7020 A1-Zn-Mg alloy welds and its effect on hot cracking and tensile properties显示文摘 | Janaki Ram G D Mitra T K Shankar V | 2003 | Journal of Ma- terials Processing Technology2003，142，： | 1 |
| 12 | Control of laves phase in incol718 GTA welds with current pulsing显示文摘 | Janaki Ram G D Venugopal Reddy A Prasad Rao K | 2004 | Science and Technology of Welding and Joining2004，9，5： | 1 |
| 13 | Mierostrueture and tensile properties of Ineonel 718 pulsed Nd-YAG laser welds显示文摘 | Janaki Ram G D Venugopal Reddy A Prasad Rao K | 2005 | Journal of Materials Processing Technology2005，167，： | 1 |
| 14 | Mechanicalproperties and microstructures of SiC fiber-reinforced metalmatrix composites made using ultrasonic consolidation显示文摘 | YANG Y STUCKER B E JANAKI RAM G D | 2010 | Journal of Materials Science2010，44，26： | 1 |
| 15 | Community structure and metabolism through reconstruction of microbial genomes from the environment 显示文摘 | TYSON G W CHAPMAN J HUGENHOLTZ P ALLEN E E RAM R J RICHARDSON P M SOLOVYEV V V RUBIN E M ROKHSAR D S | 2004 | Nature2004，428，6978： | 1 |
| 16 | Improvement in stress rupture properties of inconel 718 gas tungsten arc welds using current pulsing 显示文摘 | Ram G D J Reddy A V Rao K P | 2005 | Journal of Materials Sci- ence2005，40，6： | 1 |
| 17 | Micro- structural Refinemem Through Inoculation of Type 7020A1-Zn-Mg Alloy Welds and Its Effect on Hot Crack- ing and Tensile Properties 显示文摘 | RAM G D J M1TRA T K SHANGKAR V | 2003 | Joumal of Materials Processing Technology2003，142，1： | 1 |
| 18 | Knowledge-intensive collaborative decision support for design processes:A hybrid decision support model and agent显示文摘 | Xuan F Zha Ram D Sriram Marco G Fernandez | 2008 | Computers in Industry2008，59，： | 1 |
| 19 | Improvement in corrosion resistance of friction stir welded aluminum alloys with micro arc oxidation coatings显示文摘 | Prasad Rao K Janaki Ram G D Stucker B E | 2008 | Scripta Mater2008，58，： | 1 |
| 20 | Improvement in Corrosion Resistance of Friction Stir Welded Aluminum Alloys with Micro-arc Oxidation Coatings显示文摘 | PRASAD Rao K JANAKI Ram G D STUCKER B E | 2008 | Scripta Materialia2008，58，： | 1 |
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