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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 | Firm size and the gains from acquisitions显示文摘 | Sara B Moeller Frederik P Schlingemann René M Stulz | 2004 | Journal of Financial Economics2004，，2： | 1 |
| 3 | Wealth Destruction on a Massive Scale? A Study of Acquiring - Firm Returns in the Recent Merger Wave 显示文摘 | Sara B Moeller Frederik P Schlingemann Ren6 M Stulz | 2005 | Journal of Finance2005，60，2： | 1 |
| 4 | A new cost-effec- tive polymeric film containing an Eu (III) complex acting as UV protector and down-converter for Si-based solar cells and modules显示文摘 | Tania M H Joaquin S Sara G P | 2015 | Solar Energy Materials and Solar Cells2015，136，： | 1 |
| 5 | Bilateral sudden sensorineural hearing loss:review显示文摘 | SARA S A TEH B M FRIEDLAND P | 2014 | J Laryngol Otol2014，128，： | 1 |
| 6 | Firm size and the gains from acquisitions 显示文摘 | Frederik P Schlingemann Rene M Stulz | 2004 | Journal of Financial Economics2004，，73： | 1 |
| 7 | 显示文摘 | Francesca P Sara M Luigi T | 2008 | Water Research2008，156，： | 1 |
| 8 | A headspace solid-phase microextraction gas-chromatographic mass-spectrometric method to quantify hexanal in butter during storage as marker of lipid oxidation显示文摘 | SARA P SILVIA S LUCA M C | 2011 | Food Chemistry2011，127，2： | 1 |
| 9 | Characterization of polyploid wheat genomic diversity using a high-density 90 000 single nucleotide polymorphism array 显示文摘 | Wang SC Debbie W Kerrie F Alexandra A Shiaoman C Bevan EH Marco M Silvio S Sara GM Luigi C Anna MM Alex W Stuart S Gary B Ralf W Joerg P International Wheat Genome Sequencing Consortium Morten L Diane M Rudi A Rudy D Gina BG Abraham K Alina RA Catherine F Jerome S Michele M Curtis P Luo MC Jan DMM Jorge D Martin G Roberto T Cindy L Ivan M Colin C Keith JE Matthew H Eduard A | 2014 | Plant Biotechnol J2014，12，： | 1 |
| 10 | Changes in the expression of melatonin receptors induced by melatonin treatment in hepatocarcinoma HepG2 cells显示文摘 | Sara C P Javier M R Andres G P | 2009 | J Pineal Res2009，47，2： | 1 |
| 11 | Dissolved esterase activity as a tracer ofphytoplankton lysis: evidence of high phytoplankton lysis rates in the northwestern Mediterranean 显示文摘 | Agusti S SaRa M P Mura M P | 1998 | Limnology Oceanography1998，43，： | 1 |
| 12 | Bilateral sudden sensorineural hearing loss: review显示文摘 | S A Sara B M Teh P Friedland | 2013 | The Journal of Laryngology & Otology2013，，1： | 1 |
| 13 | Rffects of short supramaximal exercise on hemorheology in sickle cell trait carriers显示文摘 | Cormes P Sara F Hardy-Dessources M D | 2006 | Eur J Appl Physiol2006，97，2： | 1 |
| 14 | Ankylosing neurogenie myositis ossifieans of the hip An enhancedv olumetric CT study显示文摘 | Carlier R Y Sara D M Parva P | | 0，，03： | 1 |
| 15 | Synthesis and inhibitory activity of thymidine analogues targeting mycobacterium tuberculosis thymidine monophosphate kinase显示文摘 | Sara V P Helene M L Olivier H | | 0，，19： | 1 |
| 16 | A methodology to design arbitrar- y failure detectors for distributed protocols 显示文摘 | Roberto B Jean M H Sara T P | 2008 | Journal of Sys- tems Architecture2008，54，7： | 1 |
| 17 | Bilateral sudden sensorineural hearing loss:review显示文摘 | SARA S A TEH B M FRIEDLAND P | 2013 | J Laryngol Otol2013，128，： | 1 |
| 18 | Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo 显示文摘 | Lee P Sara M Lefer D J Factor SM Walsh K Kitsis RN | 2003 | Am J Physiol Heart Circ Physiol2003，284，2： | 1 |
| 19 | Does the frequency of paracolos- tomy hernias depend on the position of the colostomy in the abdominal wall 显示文摘 | Ortiz H Sara M J Armendariz P | 1994 | Int J Colorectal Dis1994，9，2： | 1 |
| 20 | Clinical transplantation of a tissue-engineered airway显示文摘 | Paolo Macchiarini Philipp Jungebluth Tetsuhiko Go M Adelaide Asnaghi Louisa E Rees Tristan A Cogan Amanda Dodson Jaume Martorell Silvia Bellini Pier Paolo Parnigotto Sally C Dickinson Anthony P Hollander Sara Mantero Maria Teresa Conconi Martin A Birchall | 2008 | The Lancet2008，，9655： | 1 |
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