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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 | Transendoscopic uhrasonography with miniprobes 显示文摘 | Abad R Varas M J Espinos JC | 2001 | Rev Esp Enferm Dig2001，93，4： | 1 |
| 3 | Modeling of mini-proinsulin production on Pichia pastoris using the AOX promoter显示文摘 | Jose M P Laura Varas | 2003 | Biotechnol Lett2003，22，： | 1 |
| 4 | Fluorescent protein-cell labeling and its application in time-lapse analysis of hematopoietic differentiation显示文摘 | Stadtfeld M Varas F Graf T | 2005 | Methods Mol Med2005，105，： | 1 |
| 5 | Surgical acquired aganglionosis : myth or reality? 显示文摘 | Bag M J Saez T Varas J | 2014 | Pediatr Surg Int2014，30，8： | 1 |
| 6 | Biotechnological applications of serpentine soil bacteria for phytoremediation of tracemetals显示文摘 | Rajkumar M Vara Prasad M N Freitas H | 2009 | Crit Rev Biotechno2009，29，： | 1 |
| 7 | Ghrelin increases anxiety-like behavior and memory retention in rats 显示文摘 | CARLINI V P MONZON M E VARAS M M | 2002 | Biochem Bioph Res Co2002，299，： | 1 |
| 8 | Dehydrogenationand oxydehydrogenation of paraffins to olefins 显示文摘 | Bhasin M M Mccain J H Vara B V | 2001 | Applied Catalysis A:General2001，221，： | 1 |
| 9 | 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 |
| 10 | 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 |
| 11 | 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 |
| 12 | Cloning of genes overning the deoxysugar portion of the erythromycin biosynthesis pathway in Saccharopolyspora erythraea (Streptomyces erythreus)显示文摘 | Vara J Lewandowska-Skarbek M Wang YG | 1989 | J Bacteriol1989，171，11： | 1 |
| 13 | Cellular automaton model for evacuation process with obstacles显示文摘 | Varas A Cornejo M D Mainemer D | 2007 | Physica A2007，382，： | 1 |
| 14 | 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 |
| 15 | Appearance and development of lymphoid cellsin the chicken (Gallus gallus) caecal tonsil 显示文摘 | Gomez M M Fonfria J Varas A | 1998 | Anat Rec1998，250，： | 1 |
| 16 | Cellular automaton model for evacuation process with obstacles显示文摘 | VARAS A CORN MAINEMER D | 2007 | Physica A2007，382，： | 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 | Musashi 2 is a regulator of the HSC compartment identified by a retroviral insertion screen and knockout mice显示文摘 | de-Andres-Aguayo L Varas F Kallin E M | | 0，，03： | 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 | Ghrelin increases anxiety-like behavior and memory retention in rats显示文摘 | CARLINI V P MONZON M E VARAS M M | 2002 | Biochem Biophys Res Commun2002，299，5： | 1 |
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