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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 | Long-term riskof mortality after acute kidney injury in patientswith sepsis: a contemporary analysis 显示文摘 | Lopes JA Fernandes P Jorge S | 2010 | BMC Nephrol2010，11，1： | 1 |
| 3 | A review of volatile analytical methods for determining the botanical origin of honey 显示文摘 | Luis F C G Jorge A P Louis S S | 2007 | Food Chem2007，103，： | 1 |
| 4 | Order and disorder in product innovation,models显示文摘 | Miguel P C Jorge F S | 2003 | Creativity and Innovation Management2003，12，3： | 1 |
| 5 | Fiberoptic hot-wire flowmeter based on a metallic coated hybrid long period grating/fiber Bragg grating structure显示文摘 | Caldas P Jorge P A S Rego G | 2011 | Applied Optics2011，50，17： | 1 |
| 6 | 显示文摘 | Stephanie V Isabel P S Jorge P J | 2007 | Langmuir2007，23，： | 1 |
| 7 | Application of sequential injection - monosegmented flow analysis (SI - MSFA) to-spectrophotometric determination of sulfide in simulated waters samples 显示文摘 | Marcelo S P Silva C X Jorge C M | 2003 | Talanta2003，60，： | 1 |
| 8 | Influence of grain orientation on the local deformation mode induced by cavita- tions erosion in a CuSnNi alloy 显示文摘 | Jorge S Michael P Claudia B | 2014 | Wear2014，316，12： | 1 |
| 9 | Fine-mapping of the intestinal receptor locus for enterotoxigenic Eschefichia coli F4ac on porcine chromosome 13显示文摘 | Python P Jorg H Neuenschwander S | 2002 | Anim Genet2002，33，6： | 1 |
| 10 | Development of Intelligent Multisensor Surveillance System with Agents显示文摘 | Juan P Jorge G S | 2007 | Robotics and Autonomous Systems2007，55，： | 1 |
| 11 | Analysis of octyl - and nonylphenol and their ethoxylates in water and sediments by liquid chromatography/tandem mass spectrometry 显示文摘 | Jorge E L R Isabelle S A Clifford P R | 2003 | Analytical Chemistry2003，75，18： | 1 |
| 12 | Combined effect of bacteriocins on the survival of various Listeria species in broth and meat system显示文摘 | GRACIELA V JORGE P FERNANDO S | 2000 | Curt Microbiol2000，41，6： | 1 |
| 13 | A mndomised trial to compare the pharmacokinctic, pharmacodynamic, and antiviral effects of peginterferon alfa -2b in patients with chronic hepatitis C 显示文摘 | Mareelo S Jorge P Cutler D | 2006 | J Hepatol2006，45，： | 1 |
| 14 | A review of volatile ana- lytical methods for determining the botanical origin of honey 显示文摘 | Luis F C G Jorge A P Louis S S | 2007 | Food Chemistry2007，103，： | 1 |
| 15 | Higher order modeling of continua by finite element, boundary-ele- ment, meshless and wavelet methods 显示文摘 | Basu P K Jorge A B Badri S | 2003 | Computers and Mathematics with Applications2003，46，3： | 1 |
| 16 | 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 |
| 17 | 查看详情显示文摘 | Boscolo P R S Menossi M Jorge R A | | 0，，02： | 1 |
| 18 | Acute kidney injury in intensive care unit patients:a comparison between the RIFLE and the Acute Kidney Injury Network classifications 显示文摘 | Lopes JA Femandes P Jorge S | 2008 | Crit Care2008，12，4： | 1 |
| 19 | T cell recognition andkilling of vascular smooth muscle cells in acute coro-nary syndrome显示文摘 | Sergey P Kayoko S Jorg J | 2006 | Circulation Research2006，98，6： | 1 |
| 20 | A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa - 2b in patients with chronic hepatitis C 显示文摘 | Marcelo S Jorge P Cutler D | 2006 | J Hepatol2006，45，： | 1 |
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