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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 | Experimental Analysis of Fluid-filled Aluminium Tubes Subjected to High- velocity Impact显示文摘 | Vara D Lopez-Puente J | 2009 | International Journal of Impact Engineering2009，36，： | 1 |
| 3 | Experimental Analysis of Fluid- filled Aluminum Tubes Subjected to High- velocity Impact 显示文摘 | Varas D L6pez- Puente J Zaera R | 2009 | International Journal of Impact Engineering2009，36，1： | 1 |
| 4 | Numerical Modeling of Partially Filled Aircraft Fuel Tanks Submitted to Hydrody- namic Ram 显示文摘 | Varas D Zaera R Lopez- Puente J | 2012 | Aerospace Science and technology2012，16，1： | 1 |
| 5 | Cellular automaton model for evacuation process with obstacles 显示文摘 | VARAS A CORNEJO M D MAINEMER M | 2007 | Physica A2007，382，2： | 1 |
| 6 | Numerical modeling of the hydrodynamic ram phenomenon 显示文摘 | Varas D Zaera R Lrpez-Puente J | 2009 | International Journal of Impact Engineering2009，36，3： | 1 |
| 7 | Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation显示文摘 | Ana Maria Sánchez Sophie Malagarie-Cazenave Nuria Olea Diana Vara Antonio Chiloeches Inés Díaz-Laviada | 2007 | Apoptosis2007，，11： | 1 |
| 8 | Pancreatic endocrine tu-mors or apudomas显示文摘 | Varas M Gornals J Ponseti JM AlastruèA Durán C Llevaria C Ballesta C Díez Caballero A Artigas V | 2011 | Rev Esp Enferm Dig2011，103，： | 1 |
| 9 | Cellular automaton model for evacuation process with obstacles显示文摘 | Varas A Cornejo M D Mainemer D | 2007 | Physica A: Statistical Mechanics and its Applications2007，382，2： | 1 |
| 10 | Zaera Experimental analysis of fluid-filled aluminium tubes subjected to high-velocity im- pact 显示文摘 | VARAS D LOPEZ J P R | 2009 | International Journal of Impact Engineering2009，36，： | 1 |
| 11 | Cellular automaton model for evacuation process with obstacles显示文摘 | Varas A Cornejo M D Mainemer D | 2007 | Physica A2007，382，： | 1 |
| 12 | Appearance and development of lymphoid cells in the chicken (Gallus gallus) caecal tonsil显示文摘 | Gomez D M Fonfria J Varas A | 1998 | Anat Rec1998，250，2： | 1 |
| 13 | Experimental analysis of fluid-filled aluminium tubes subjected to high- velocity impact 显示文摘 | VARAS D LO'PEZ-PUENTE J ZAERA R | 2009 | International Journal of Impact Engineering2009，36，： | 1 |
| 14 | Cloning and expression of a puromycin N-acetyl transferase gene from Streptomyces alboniger in Streptomyces lividans and Escherichia coli显示文摘 | Vara J Malpartida F Hopwood D A | 1985 | Gene1985，33，2： | 1 |
| 15 | Cellular automaton model for evacuation process with obstacles显示文摘 | VARAS A CORN MAINEMER D | 2007 | Physica A2007，382，： | 1 |
| 16 | Molecular analysis of the pac gene encoding a puromycin N-acetyl transferase from Streptomyces alboniger显示文摘 | Lacalle R A Pulido D Vara J | 1989 | Gene1989，79，2： | 1 |
| 17 | Cellular automaton model for evacuation process with obstacles 显示文摘 | Varas A Cornejo M D Mainemer D | 2007 | Physica A2007，382，2： | 1 |
| 18 | Estimating reference evapo transpiration (ET0) using numerical weather forecast data in central Chile显示文摘 | Silva D Meza F J Varas E | 2010 | Journal of Hydrology2010，382，： | 1 |
| 19 | Cellular automaton model for evacuation process with obstacles 显示文摘 | VARAS A CORNEJO M D MAINEMER D | 2007 | Physica A2007，382，2： | 1 |
| 20 | Cellular automaton model for evacuation process with obstacles显示文摘 | VARAS A CORNEJO M D MAINEMER D | 2007 | Physica A2007，，382： | 1 |
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