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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 | Heparanase: a new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes显示文摘 | Sommerfeldt N Beckhove P Ge Y Sehutz F Choi C Bucur M Domsehke C Sohn C Sehneeweis A Rom J Poll- mann D Leneht D Vlodavsky I Sehirrmaeher V | 2006 | Cancer Res2006，66，15： | 1 |
| 3 | Continuous positive airway pressure in sleep apnea prevents new vascular events after ischemic stroke显示文摘 | Martínez-García MA Galiano-Blancart R Román-Sánchez P | | 0，，： | 1 |
| 4 | ASchum perian Model of the Product Life Cycle显示文摘 | Segerst rom P Anant T and Dinopoulos E | 1990 | American Economic Review1990，，12： | 1 |
| 5 | In hindsight, life flows from left to right显示文摘 | Julio Santiago Antonio Román Marc Ouellet Nieves Rodríguez Pilar Pérez-Azor | 2010 | Psychological Research PRPF2010，，1： | 1 |
| 6 | Sonographic morphology of infiltrating breast carc inoma:relationship with the shape of the hyaluronanextracellular matrix显示文摘 | Vignal P Meslet MR Roméo JM | 2002 | J Ultrasound Med2002，21，5： | 1 |
| 7 | Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease 显示文摘 | Soler - Catalufia J J Martinez - Garca MA Rom(m S6nchez P | 2005 | Thorax2005，60，11： | 1 |
| 8 | Increased incidence of multi-drugresistant tuberculosis in diabetic patients on the Bellevue Chest Service 1987 to 1997显示文摘 | Bashar M Alcabes P Rom WN | 2001 | Chest2001，120，5： | 1 |
| 9 | Effect iveness of lo cal anesthesia in pediatric dental pr act ice显示文摘 | Nakai Y Milg rom P Manel L | | 0，，55： | 1 |
| 10 | Atherosclerotic plaque regression:fact or fiction显示文摘 | Shanmugam N Rom á n-Rego A Ong P | | 0，，04： | 1 |
| 11 | Dementia Subtypes in China:Prevalence in Beijing,Xian,Shangha,i and Chengdu显示文摘 | Zhang ZX Zahner GE P Román GC | 2005 | ArchNeuro l2005，62，： | 1 |
| 12 | p53 codon 72 polymorphism and human papillomavirus type in relation to cervical cancer in South African women 显示文摘 | Pegoraro R J Rom L Lanning P A | 2002 | lnt J Gynecol Cancer2002，12，4： | 1 |
| 13 | Increased incidence of muhidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service ,1987 to 1997 显示文摘 | Bashar M Alcabes P Rom WN | 2001 | Chest2001，120，5： | 1 |
| 14 | Bone graft ing and new composite biosyn- thet ic graft materials 显示文摘 | Lane JM Bo st rom M P | 1998 | Inst rCo rtse L ect1998，47，5： | 1 |
| 15 | Biological subtypes of triple-negative breast cancer are associated with distinct morphological changes and clinical behaviour 显示文摘 | ELSAWAF Z SINN H P ROM J | 2013 | Breast2013，22，5： | 1 |
| 16 | J Mol Struct显示文摘 | Castillo O Luque A Romān P | 2001 | 570:1812001，570，： | 1 |
| 17 | Biosorption of Cr(III) using in natura and chemically treated tropical peats显示文摘 | BATISTAA A P S ROM O L P C ARGUELHO M L P M | 2009 | Journal of Hazardous Materials2009，163，23： | 1 |
| 18 | The association between bronchiectasis,systemic inflammation,and tumor necrosis factor alpha显示文摘 | Martínez-García MA Perpiá-Tordera M Román-Sánchez P | 2008 | Arch Bronconeumol2008，44，1： | 1 |
| 19 | Biosorption of Cr(III) using in natura and chemically treated tropical peats 显示文摘 | BATISTAA A P S ROM O L P C ARGUELHO M L P M | 2009 | Journal of Hazardous Materials2009，163，： | 1 |
| 20 | Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease 显示文摘 | Soler-Catalufia JJ Marttnez-Garcfa MA Rom~in S~tnchez P | 2005 | Thorax2005，60，11： | 1 |
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