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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 | Block matching algorithm for motion estimation based on Artificial Bee Colony (ABC)显示文摘 | Erik Cuevas Daniel Zaldívar Marco Pérez-Cisneros Humberto Sossa Valentín Osuna | 2012 | Applied Soft Computing Journal2012，，： | 1 |
| 3 | Multilayer neural network applied to phase and depth recovery from fringe patterns 显示文摘 | Cuevas F J Servin M Stavroudis O N | 2000 | Opt Commun2000，181，： | 1 |
| 4 | Gene promoter hypermethylation in oral rinses of leukoplakia patients-a diagnostic and/or prognostic tool显示文摘 | López M Aguirre JM Cuevas N | | 0，，16： | 1 |
| 5 | Isolation and selection of a highly tolerant microbial consortium with potential for PAH biodegradation from heavy crude oil-contaminated soils 显示文摘 | ZAFRA G ABSAL 6 N ~ E CUEVAS M D C | 2014 | Water Air and Soil Pollution2014，225，： | 1 |
| 6 | Ca2+/calmodulin-dependent modulation of cell cycle elements pRb and p27kip1 involved in the enhanced proliferation of lymphoblasts from patients with Alzheimer dementia显示文摘 | de las Cuevas N Urcelay E Hermida OG | 2003 | Neurobiol Dis2003，13，3： | 1 |
| 7 | MEKK1 reg- ulates calpain - dependent proteolysis of focal adhesion proteins for rear - end detachment of migrating fi broblasts显示文摘 | CUEVAS B D ABELL A N WITOWSKY J A | 2003 | EMBO J2003，22，13： | 1 |
| 8 | Wastewater Fermentation and Nutrient Removal in Sequencing Batch Reactors显示文摘 | óscar González-Barceló Simón González-Martínez | 1998 | Water Science and Technology1998，38，1： | 1 |
| 9 | Epidemiology of rotavirus diarrhea in Iranian children 显示文摘 | Khalili B Cuevas LE Reisi N | 2004 | J Med Virol2004，73，2： | 1 |
| 10 | Water-stable ammonium-terminated carbosilanedendrimers as efficient antibacterial agents 显示文摘 | RASINES B HERNANDEZ-ROS J M DE LAS CUEVAS N | 2009 | Dalton Trans2009，，40： | 1 |
| 11 | LED fluo-rescence microscopy for the diagnosis of pulmonary tuberculosis:a multi-country cross-sectional evaluation显示文摘 | CUEVAS LE AL-SONBOLI N LAWSON L | 2011 | PLoS Med2011，8，00： | 1 |
| 12 | Involvement of polyamines in plant response to abiotic stress显示文摘 | Rubén Alcázar Francisco Marco Juan C. Cuevas Macarena Patron Alejandro Ferrando Pedro Carrasco Antonio F. Tiburcio Teresa Altabella | 2006 | Biotechnology Letters2006，，23： | 1 |
| 13 | Modula- tion of immune function by polyphenols: Possible contribution of epigenetic factors显示文摘 | CUEVAS A SAAVEDRA N SALAZAR L A | 2013 | Nutrients2013，5，7： | 1 |
| 14 | LEDfluorescence microscopy for the diagnosis of pulmonarytuberculosis: a multi-country cross-sectional evaluation 显示文摘 | Cuevas LE Al-Sonboli N Lawson L | 2011 | PLoS Med2011，8，7： | 1 |
| 15 | Gene promoter hypermethylation in oral rinses of leukoplakia patients-a diagnostic and/or prognostic tool显示文摘 | Lopez M Aguirre JM Cuevas N | 2003 | Eur J Cancer2003，39，16： | 1 |
| 16 | No association between GSTP1 gene aberrant promoter methylation and prognosis in surgically resected hepatocellular carcinoma patients from the Basque country(No rthern Spain)显示文摘 | A nzo la M Cuevas N Lopez-M artinezM | 2003 | Liver Int2003，23，4： | 1 |
| 17 | Natural field induced polarization for mapping of deep mineral deposits: Afield example from Arizona显示文摘 | Gasperikova E Cuevas N H Morrison H F | 2005 | Geophysics2005，70，6： | 1 |
| 18 | JAK-STAT signal inhibition regulates competition in the Drosophila testis stem cell Niehe显示文摘 | Issigonis M Tulina N de Cuevas M | 2009 | Science2009，326，5949： | 1 |
| 19 | The signature of chemical valence in the electrical conduction through a single-atom contact 显示文摘 | SCHEER E AGRAIT N CUEVAS J C | 1998 | Nature1998，394，： | 1 |
| 20 | Deconjugation and bile salts hydrolase activity by Bifidobacterium strains with acquired resistance to bile显示文摘 | Luis Noriega Isabel Cuevas Abelardo Margolles Clara G. de los Reyes-Gavilán | 2005 | International Dairy Journal2005，，8： | 1 |
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