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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 | Synthesis and Characterization of Some Transition Metal Complexes of N-( 2- Hydroxyl -Naphthylidene) Amino Acids显示文摘 | Praveen K S Ram N H Bhowon M G | 1996 | Inorg Met Org Chem1996，26，7： | 1 |
| 3 | Effect of highpressure treatments on mechanical and functional properties of restructured products from arrowtooth flounder(Atheresthes stomias)显示文摘 | Uresti M R Velazquez G Ramírez J | 2004 | Journal of the Science of Food Agriculture2004，84，： | 1 |
| 4 | Gas - phase oxidation of glycerol to dihydroxyacetone over tailored iron zeolites 显示文摘 | LARI G M MONDELLI C PEIREZ - RAM | 2015 | ACS Catalysis2015，5，3： | 1 |
| 5 | Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition显示文摘 | Milara J Navarro R Juan G PeiróT Serrano A Ramón M | 2012 | Thorax2012，67，2： | 1 |
| 6 | The institutional embeddedness of local inter-firm net- works:a leverage for business ereation显示文摘 | JOHANNISSON B M RAM? REZ-PASILLAS G KARLS- SON | 2002 | Entrepreneurship Regional Development2002，14，4： | 1 |
| 7 | Origin and basipetal transport of the IAA reponsible for rooting of carnation cuttings显示文摘 | Garrido G Ramón Guerrero J Angel Cano E Acosta M Sánchez-Bravo J | 2002 | Physiologia Plantarum2002，114，2： | 1 |
| 8 | 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 |
| 9 | Development of Replication Adenovirus Serotype 5 Containing the Capsid and 3C Protease Coding Regions of Foot-and-mouth Disease Virus as a Vaccine Candidate 显示文摘 | MAYR G A CHINSANG RAM J GRUBMAN M | 1999 | Virology1999，263，： | 1 |
| 10 | Partial pole placement with time delay in the receptance and the system matrices显示文摘 | Ram Y M Mottershead J E Tehrani M G | | 0，，： | 1 |
| 11 | Cost layered double hydroxides for CO2 capture:Structure evolution and regeneration显示文摘 | RAM REDDY M K XU Z P LU G Q DINIZ da COSTA J C | 2006 | Ind Eng Chem Res2006，45，22： | 1 |
| 12 | Thin SolidFilms显示文摘 | Dirks A G Wolters RAM Nellissen A J M | 1990 | 193-194(1): 2011990，193，194： | 1 |
| 13 | Economic feasibility study for wastewater treatment:A cost-benefit analysis显示文摘 | María M S Francesc H S Ramón S G | 2010 | Science of the Total Environment2010，408，20： | 1 |
| 14 | Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane显示文摘 | Barcellos-Hoff M H Aggeler J Ram T G | 1989 | Development1989，105，： | 1 |
| 15 | Role of vitamin E and phenolic compounds in the antioxidant capacity, measured by ESR, of virgin olive, olive and sunflower oils after frying显示文摘 | Quiles J L Ramírez-Tortosa M C Gómez J A | 2002 | Food Chemistry2002，76，4： | 1 |
| 16 | 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 |
| 17 | Resisting andchallenging stigma in Uganda : the role of supportgroups of people living with HIV显示文摘 | Mburu G Ram M Skovdal M | 2013 | J Int AIDS Soc2013，16，3： | 1 |
| 18 | Aflatoxin (B1, B2, G1, and G2) Contamination in Rice of Mexico and Spain, from Local Sources or Imported显示文摘 | Elena Suárez‐Bonnet Magda Carvajal Ignacio Méndez‐Ramírez Pável Castillo‐Urueta Josefina Cortés‐Eslava Sandra Gómez‐Arroyo José María Melero‐Vara | 2013 | Journal of Food Science2013，，11： | 1 |
| 19 | Constructing a finite element model of a vibratory rod from eigendata显示文摘 | Ram Y M Gladwell G M L | 1994 | J Sound and Vibration1994，169，2： | 1 |
| 20 | 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 |
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