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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 | Ground Response Curves for Rock Masses Exhibiting Strain-Softening Behavior显示文摘 | Alonso E Alejano L R Varas F Fdez-Manin G Carranza-Torres C | 2003 | Int J Numer Anal Meth Geomech2003，，27： | 1 |
| 3 | Influence of nickel content on the electrochemical behavior of Finemet type amorphous and nanocrystalline alloys显示文摘 | VARA G PIERNA A R JIMENEZ J A | 2007 | Journal of Non-Crystalline Solids2007，353，： | 1 |
| 4 | 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 |
| 5 | Expression of the rabies virus nucleoprotein in plants at high-levels and evaluation of immune responses in mice显示文摘 | Irene Perea Arango Elizabeth Loza Rubio Edith Rojas Anaya Teresa Olivera Flores Luis Gonzalez de la Vara Miguel Angel Gómez Lim | 2008 | Plant Cell Reports2008，，4： | 1 |
| 6 | 显示文摘 | Punshon G Vara D S Sales K M | 2005 | Biomaterials2005，26，32： | 1 |
| 7 | Influence of nickel content on the electrochemical behavior of Finemet type a- morphous and nanocrystalline alloys 显示文摘 | Vara G Pierna A R Garcia J A | 2007 | Journal of Non- Crystalline Solids2007，353，8910： | 1 |
| 8 | Cloning of genes governing the deoxysugar portion of the erythromycin biosynthesis pathway in Saccharopolyspora erythraea (Streptornyces erythreus ) 显示文摘 | Vara J Lewandowska-Skarbek M Wang Y G | 1989 | J Bacteriol1989，171，11： | 1 |
| 9 | Influence of nickel content on the electrochemical behavior of Finemet type amorphous and nanocrystalline alloys显示文摘 | Vara G Pierna A R Jimenez J A | 2007 | Journal of Non-Crystalline Solids2007，353，： | 1 |
| 10 | Seasonal variations in the immune system of lower vertebrates 显示文摘 | Zapata A G Varas A Torroba M | 1992 | Immunol Today1992，13，： | 1 |
| 11 | Betacyanin biosynthetic genes andenzymes are differentially induced by (a) biotic stress inAmaranthus hypochondriacus 显示文摘 | CASIQUE-ARROYO G MART NEZ-GALLARDO N DELA VARA LG | 2014 | Plos One2014，9，99： | 1 |
| 12 | Expression of the rabies virus nucleoprotein in plants at high-levels and evaluation of immune responses in mice显示文摘 | Irene Perea Arango Elizabeth Loza Rubio Edith Rojas Anaya Teresa Olivera Flores Luis Gonzalez de la Vara Miguel Angel Gómez Lim | | Plant Cell Reports0，，： | 1 |
| 13 | Ground reaction curves for rock masses exhibiting strain-softening behaviour显示文摘 | Alonso E Alejano LR Varas F Fdez-Manín G Carranza-Torres C | | 0，，13： | 1 |
| 14 | Seasonal variations in the immune system of lower vertebrates显示文摘 | ZAPATA A G VARAS A TORROBA M | 1992 | Immunology Today1992，13，： | 1 |
| 15 | Cloning of genes governing the deoxysugar portion of the erythromycin biosynthesis pathway in Saccharopolyspora erythraea ( Streptomyces erythreus )显示文摘 | Vara J Lewandowska-Skarbek M Wang Y G | 1989 | J Bacteriol1989，171，： | 1 |
| 16 | Influence of nickel content on the electrochemical behavior of finemet type amorphous and nanocrystalline alloys显示文摘 | VARA G PIERNA A R JIMENEZ J A | 2007 | Journal of Non- crystalline Solids2007，353，： | 1 |
| 17 | Appearance anddevelopment of lymphoid cells in the chicken(Gallus gallus)caecal tonsil显示文摘 | Del Moral M G Fonfria J Varas A | 1998 | The Anatomical Record1998，250，2： | 1 |
| 18 | Ce report on the clinical mmlts of a combined cellular thempy for chronic spinal cord injured patients显示文摘 | MovigKa GA Vara G Bmela JA et sl | 2009 | Spinal Cord2009，47，6： | 1 |
| 19 | Seasonal variations in the immune system of lower vertebrates显示文摘 | Zapata A G Varas A Torroba M | 1992 | Immunol Today1992，13，： | 1 |
| 20 | Reactive oxygen species: physiological roles inthe regulation of vascular cells显示文摘 | Vara D Pula G | 2014 | Current molecular medicine2014，14，9： | 1 |
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