Delta-tocotrienol enhances the anti-tumor effects of interferon alpha through reactive oxygen species and Erk/MAPK signaling pathways in hepatocellular carcinoma cells.

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

Data of ureagenesis from ammonia, glutamine and alanine, and mitochondrial aquaporin-8 expression in thioacetamide-treated hepatocytes.

We present data about the synthesis of urea from different substrates, i.e., free ammonia, glutamine and alanine in primary cultured rat hepatocytes treated or untreated with the model hepatotoxic agent thioacetamide (TAA). We also provide data about the expression of mitochondrial aquaporin-8 (mtAQP8), a hepatocyte channel protein which facilitates ammonia diffusion into mitochondria to supply the urea cycle. Ammonia-derived ureagenesis was significantly inhibited by about 30% while that from the both amino acids resulted unaffected in TAA-treated hepatocytes. Protein expression of mtAQP8 was decreased by about 80% after TAA treatment. These data can be useful for the understanding of the mechanisms of drug-induced hepatic dysfunction.

Participation of 5-lipoxygenase and LTB4 in liver regeneration after partial hepatectomy.

Regeneration is the unmatched liver ability for recovering its functional mass after tissue lost. Leukotrienes (LT) are a family of eicosanoids with the capacity of signaling to promote proliferation. We analyzed the impact of blocking LT synthesis during liver regeneration after partial hepatectomy (PH). Male Wistar rats were subjected to two-third PH and treated with zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX). Our first find was a significant increment of intrahepatic LTB4 during the first hour after PH together with an increase in 5-LOX expression. Zileuton reduced hepatic LTB4 levels at the moment of hepatectomy and also inhibited the increase in hepatic LTB4. This inhibition produced a delay in liver proliferation as seen by decreased PCNA and cyclin D1 nuclear expression 24 h post-PH. Results also showed that hepatic LTB4 diminution by zileuton was associated with a decrease in NF-ĸB activity. Additionally, decreased hepatic LTB4 levels by zileuton affected the recruitment of neutrophils and macrophages. Non-parenchymal cells (NPCs) from zileuton-treated PH-rats displayed higher apoptosis than NPCs from PH control rats. In conclusion, the present work provides evidences that 5-LOX activation and its product LTB4 are involved in the initial signaling events for liver regeneration after PH and the pharmacological inhibition of this enzyme can delay the initial time course of the phenomenon.

Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet.

Obesity is accompanied by a low-grade inflammation state, characterized by increased proinflammatory cytokines levels such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1ß). In this regard, there exists a lack of studies in hepatic tissue about the role of TNFα receptor 1 (TNFR1) in the context of obesity and insulin resistance during the progression of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to evaluate the effects of high-caloric feeding (HFD) (40% fat, for 16 weeks) on liver inflammation-induced apoptosis, insulin resistance, hepatic lipid accumulation and its progression toward nonalcoholic steatohepatitis (NASH) in TNFR1 knock-out and wild-type mice. Mechanisms involved in HFD-derived IL-1ß release and impairment of insulin signaling are still unknown, so we determined whether IL-1ß affects liver insulin sensitivity and apoptosis through TNFα receptor 1 (TNFR1)-dependent pathways. We showed that knocking out TNFR1 induces an enhanced IL-1ß plasmatic release upon HFD feed. This was correlated with higher hepatic and epididymal white adipose tissue mRNA levels. In vivo and in vitro assays confirmed an impairment in hepatic insulin signaling, in part due to IL-1ß-induced decrease of AKT activation and diminution of IRS1 levels, followed by an increase in inflammation, macrophage (resident and recruited) accumulation, hepatocyte apoptotic process and finally hepatic damage. In addition, TNFR1 KO mice displayed higher levels of pro-fibrogenic markers. TNFR1 signaling disruption upon an HFD leads to an accelerated progression from simple steatosis to a more severe phenotype with many NASH features, pointing out a key role of TNFR1 in NAFLD progression.

Attenuation of liver cancer development by oral glycerol supplementation in the rat.

PURPOSE: Glycerol usage is increasing in food industry for human and animal nutrition. This study analyzed the impact of glycerol metabolism when orally supplemented during the early stage of rat liver carcinogenesis. METHODS: Wistar rats were subjected to a 2-phase model of hepatocarcinogenesis (initiated-promoted, IP group). IP animals also received glycerol by gavage (200 mg/kg body weight, IPGly group). RESULTS: Glycerol treatment reduced the volume of preneoplastic lesions by decreasing the proliferative status of liver foci, increasing the expression of p53 and p21 proteins and reducing the expression of cyclin D1 and cyclin-dependent kinase 1. Besides, apoptosis was enhanced in IPGly animals, given by an increment of Bax/Bcl-2 ratio, Bad and PUMA mitochondrial expression, a concomitant increase in cytochrome c release and caspase-3 activation. Furthermore, hepatic levels of glycerol phosphate and markers of oxidative stress were increased in IPGly rats. Oxidative stress intermediates act as intracellular messengers, inducing p53 activation and changes in JNK and Erk signaling pathways, with JNK activation and Erk inhibition. CONCLUSION: The present work provides novel data concerning the preventive actions of glycerol during the development of liver cancer and represents an economically feasible intervention to treat high-risk individuals.

Comparison of two chemical models to induce hepatic preneoplasia in male Wistar rats.

BACKGROUND: One established model to induce hepatic preneoplasia (HP) (DEN 150) uses diethylnitrosamine (DEN) as initiator agent and 2-acetylaminofluorene (2-AAF) as a promoter drug. In addition, both chemicals cause liver cholestasis and fibrosis. AIM: We compared DEN 150 model with another adapted by us, DEN 200 to simplify the first one and to evaluate the effectiveness of both treatments to induce HP in rats. MATERIAL AND METHODS: Male Wistar rats were divided in 3 groups: controls; DEN 150 (rats received 2 doses of DEN, 150 mg/kg body weight, 2 weeks apart, and then 2-AAF, 20 mg/kg body weight, 4 doses per week during 3 weeks); and DEN 200 (rats received a single dose of DEN 200 mg/kg body weight, and 2 weeks apart 2-AAF, 20 mg/kg body weight, 2 doses per week during 3 weeks). Four hepatic enzymes, prothrombin time percentage, the number of bile ductules, total collagen amount, the number of altered hepatic foci (AHF) per liver and the percentage of liver occupied by foci were analyzed. Results. There were no differences in the number of AHF per liver between treated groups. Rats from DEN 200 group showed a significant diminution in the volume of liver occupied by foci. DEN 200 group had no fibrosis and better hemostatic conditions than DEN 150 group. Both groups developed cholestasis. CONCLUSION: In conclusion, both protocols are good alternatives to induce HP in rats and the new protocol proposed is an effective and a simple methodology to provide subclinic states of liver cancer.

FoxO3a nuclear localization and its association with ß-catenin and Smads in IFN-α-treated hepatocellular carcinoma cell lines.

Interferon-α2b (IFN-α2b) reduces proliferation and increases apoptosis in hepatocellular carcinoma cells by decreasing ß-catenin/TCF4/Smads interaction. Forkhead box O-class 3a (FoxO3a) participates in proliferation and apoptosis and interacts with ß-catenin and Smads. FoxO3a is inhibited by Akt, IκB kinase ß (IKKß), and extracellular-signal-regulated kinase (Erk), which promote FoxO3a sequestration in the cytosol, and accumulates in the nucleus upon phosphorylation by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (p38 MAPK). We analyzed FoxO3a subcellular localization, the participating kinases, FoxO3a/ß-catenin/Smads association, and FoxO3a target gene expression in IFN-α2b-stimulated HepG2/C3A and Huh7 cells. Total FoxO3a and Akt-phosphorylated FoxO3a levels decreased in the cytosol, whereas total FoxO3a levels increased in the nucleus upon IFN-α2b stimulus. IFN-α2b reduced Akt, IKKß, and Erk activation, and increased JNK and p38 MAPK activation. p38 MAPK inhibition blocked IFN-α2b-induced FoxO3a nuclear localization. IFN-α2b enhanced FoxO3a association with ß-catenin and Smad2/3/7. Two-step coimmunoprecipitation experiments suggest that these proteins coexist in the same complex. The expression of several FoxO3a target genes increased with IFN-α2b. FoxO3a knockdown prevented the induction of these genes, suggesting that FoxO3a acts as mediator of IFN-α2b action. Results suggest a ß-catenin/Smads switch from TCF4 to FoxO3a. Such events would contribute to the IFN-α2b-mediated effects on cellular proliferation and apoptosis. These results demonstrate new mechanisms for IFN-α action, showing the importance of its application in antitumorigenic therapies.

Interferon-α2b and transforming growth factor-ß1 treatments on HCC cell lines: Are Wnt/ß-catenin pathway and Smads signaling connected in hepatocellular carcinoma?

Wnt/ß-catenin pathway is often dysregulated in hepatocellular carcinoma (HCC). Activated ß-catenin accumulates in the cytosol and nucleus and forms a nuclear complex with TCF/LEF factors like TCF4. Interferon-α (IFN-α) has recently been recognized to harbor therapeutic potential in prevention and treatment of HCC. Transforming Growth Factor-ß1 (TGF-ß1) is a mediator of apoptosis, exerting its effects via Smads proteins. One mode of interaction between Wnt/ß-catenin and TGF-ß1/Smads pathways is the association of Smads with ß-catenin/TCF4. In this study we analyzed the effects of IFN-α2b and TGF-ß1 treatments on Wnt/ß-catenin pathway, Smads proteins levels, ß-catenin/TCF4/Smads interaction and proliferation and apoptotic death in HepG2/C3A and Huh7 cell lines. IFN-α2b and TGF-ß1 attenuated Wnt/ß-catenin signal by decreasing ß-catenin and Frizzled7 receptor proteins contents and the interaction of ß-catenin with TCF4. Truncated ß-catenin form present in C3A cell line also diminished after treatments. Both cytokines declined Smads proteins and their interaction with TCF4. The overall cellular response to cytokines was the decrease in proliferation and increase in apoptotic death. Treatment with Wnt3a, which elevates ß-catenin protein levels, also generated the increment of Smads proteins contents when comparing with untreated cells. In conclusion, IFN-α2b and TGF-ß1 proved to be effective as modulators of Wnt/ß-catenin pathway in HCC cell lines holding both wild-type and truncated ß-catenin. Since the inhibition of ß-catenin/TCF4/Smads complexes formation may have a critical role in slowing down oncogenesis, IFN-α2b and TGF-ß1 could be useful as potential treatments in patients with HCC.

Effect of Ligaria cuneifolia catechin- and quercetin-enriched fractions on hemorheology and plasma cholesterol.

UNLABELLED: We tested the in vivo and the in vitro effects of both Ligaria cuneifolia catechin- and quercetin-enriched fractions on erythrocyte shape and deformability, and on plasma cholesterol level. For in vivo studies, adult male Wistar rats were randomized in three experimental groups which received intraperitoneally, once a day, 3 days: CONTROL: saline solution (C; n = 6); catechin from L. cuneifolia, 0.60 mg/100 g body weight (CLc; n = 6), or quercetin from L. cuneifolia, 2.3 mg/100 g body weight (QLc; n = 6). For in vitro studies, blood samples obtained from male Wistar rats were divided into three fractions, which were incubated with saline solution (C), catechin (CLc; n = 5) and quercetin (QLc; n = 5), in a concentration equivalent to 0.60 mg/100 g body weight, and 2.3 mg/100 g body weight, respectively. CLc significantly reduced the rigidity index due to a diminished mean concentration volume. QLc induced erythrocyte rigidization (less deformability), thus increasing blood viscosity. Neither of the two treatments produced any changes in plasmatic or biliary excretion of cholesterol. Opposite results were observed in rigidity index with CLc and QLc. In vitro studies showed an interaction of both CLc and QLc with the erythrocyte membrane, which induced changes in the erythrocyte shape from discocyte to stomatocyte.

Cross-talk between IFN-alpha and TGF-beta1 signaling pathways in preneoplastic rat liver.

Interferon-gamma/transforming growth factor-beta (IFN-gamma/TGF-beta) pathways have opposite effects on diverse cellular functions. However, little is known about interactions between IFN-alpha/TGF-beta. In previous studies, we showed that IFN-alpha2b increases TGF-beta(1) production and secretion in hepatocytes from preneoplastic rat livers. Here, the interaction between IFN-alpha/TGF-beta(1) pathways was explored. We observed a positive cross-talk between IFN-alpha and TGF-beta(1) signaling, with activation of both pathways. p300 protein levels in hepatocytes from preneoplastic livers were enough to interact with both activated Stat1 and Smad2/3. Besides, Smad7 was not directly related with TGF-beta(1) and IFN-alpha signals. Interestingly, we reported the novel finding that the autocrine TGF-beta(1) up-regulates TGF-betaRII at protein and mRNA levels. In conclusion, the intracellular signals triggered by IFN-alpha2b and by autocrine TGF-beta(1) are integrated at the nuclear level, where activated Stat1 and Smad2/3 are capable of interact with p300, present in no restrictive cellular amounts.

Hepatocytes isolated from preneoplastic rat livers are resistant to ethacrynic acid cytotoxicity.

Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics, such as several cytostatic drugs, through conjugation with glutathione (GSH). Pi class GST (GST P) liver expression is associated with preneoplastic and neoplastic development and contributes with the drug-resistance phenotype. Ethacrynic acid (EA) is an inhibitor of rat and human GSTs. In addition, causes lipid peroxidation in isolated rat hepatocytes. Therefore, we decided to evaluate the role of the GST/GSH system in isolated hepatocytes from preneoplastic rat livers (IP) in the presence of EA and determine the cytotoxicity of the drug. Our results showed a resistance to the toxic effects of EA since viability and cellular integrity values were significantly higher than control. Initial levels of thiobarbituric acid reactive substances (TBARS) in IP hepatocytes were significantly higher than control and the presence of EA did not change TBARS levels. A diminution in intracellular total GSH was observed by treating with EA isolated hepatocytes from both groups. However, the initial total GSH levels were higher in IP hepatocytes than in control. Immunoblotting analysis showed the presence of GST P in IP animals only. Although alpha and mu class isoenzymes levels were decreased in IP hepatocytes, total GST activity was 1.5-fold higher than in control. In addition, multidrug-resistance protein 2 (Mrp2) showed fivefold decreased levels in IP hepatocytes. In conclusion, increased total GSH, decreased Mrp2 levels and the presence of GST P could be critical factors involved in the resistance of IP hepatocytes to the toxicity of EA.

Involvement of reactive oxygen species on the apoptotic mechanism induced by IFN-alpha2b in rat preneoplastic liver.

Interferon-alpha2b (IFN-alpha2b) is an important component in the preventive treatment of patients who have severe hepatic illness such as hepatitis B or C and hepatocarcinomas. In a previous work, using a rat liver preneoplastic model, we have demonstrated that IFN-alpha2b reduces the number and volume of altered hepatic foci (AHF) inducing apoptosis through a mechanism mediated by TGF-beta(1). In this study, the implication of hepatocytes redox status of IFN-alpha2b-treated preneoplastic liver in the TGF-beta(1)-induced apoptotic death was analyzed. Results indicate that IFN-alpha2b induces hepatocytic TGF-beta(1) production and secretion by induction of reactive oxygen species (ROS) formation through the activation of a membrane bound NADPH oxidase complex. TGF-beta(1), in turn, reduces hepatocytes antioxidant defenses and induces programmed cell death. On the other hand, it was also demonstrated that treatment of rats with IFN-alpha2b plus a ROS scavenger such as ascorbic acid, abolishes the apoptotic effect of IFN-alpha2b in rat preneoplastic livers, leading to an increase of the foci volume. In conclusion, these findings strongly suggest that ROS have a fundamental role as signaling and/or regulator molecules in the IFN-alpha2b-induced apoptosis in hepatic preneoplastic cells.

Interferon alfa-2b triggers transforming growth factor-beta-induced apoptosis on preneoplasticliver.

Considerable expectations to prevent hepatocellular carcinoma (HCC) appearance are connecte with the use of Inferon alpha (IFN alpha) in antiviral treatment of the hepatitis B or C. Several studies have reported that the incidence of HCC may b reduced after IFN therapy in patients with chronic B or C hepatitis although its real preventive efffect is still debatable. The purpose of the studies from our laboratory was to evaluate the action of IFN alpha2b on preneoplastic foci in a two-phase model of preneoplasia development in rat. We demonstrated that IFN-alpha2b administration significantly decreased both number and volume percentage of altered hepatitis foci (AHF). This reduction could be explained by an induced programmed cell death in the foci. This apoptotic effect of IFN-alpha2b on preneoplastic liver foci was mediated by the production of endogenous TGFbeta1 from hepatocytes acting by a paracrine/autocrine way. Further studies confirmed that these results were a consequence of the perturbation of the redox status induced by the IFN-2b. In conclusion, IFN-alpha2b couldenhance the proapoptotic effects of TGFbeta1, in early stages of hepatocarcinogenesis, which could be highly beneficial in cancer therapy.

Time-dependent onset of Interferon-alpha2b-induced apoptosis in isolated hepatocytes from preneoplastic rat livers.

We have already demonstrated that interferon alfa-2b (IFN-alpha2b) induces apoptosis in isolated hepatocytes from preneoplastic rat livers via the secretion of transforming growth factor beta(1) (TGF-beta(1)), and this process is accompanied by caspase-3 activation. The aim of this study was to further investigate the mechanism of this activation. Isolated hepatocytes from preneoplastic livers induced DNA fragmentation in response to IFN-alpha2b, which was completely blocked when anti-TGF-beta(1) was added to the culture media. IFN-alpha2b mediated radical oxygen species (ROS) production that preceded the loss of mitochondrial transmembrane potential (DeltaPsi), release of cytochrome c, and activation of caspase-3. Bax levels increased in a time-dependent fashion, and Bcl-x(L) was down-regulated in the early hours of IFN-alpha2b treatment. The delayed translocation of Bid into the mitochondria was in concordance with late caspase-8 activation. In conclusion, endogenous TGF-beta(1) secreted under IFN-alpha2b stimulus seems to induce cytochrome c release through a mechanism related to Bcl-2 family members and loss of mitochondrial DeltaPsi. Bax protein could be responsible of the release of cytochrome c during the initial hours of IFN-alpha2b-induced apoptosis via TGF-beta(1). Activated Bid by caspases could amplificate the mitochondrial events, enhancing the release of cytochrome c.

El Factor de Crecimiento Transformante beta 1 y su relación con el proceso de apoptosis durante hepatocarcinogénesis química en ratas

Estudio de los mecanismos involucrados en la apoptosis inducida por Interferón alfa-2b (IFN- 2b) de focos preneoplásicos en hígados de ratas. La caracterización de dichos mecanismos permitirá avanzar en el conocimiento de los procesos de hepatocarcinogénesis y su supresión mediante el uso de agentes inmunomoduladores con propiedades apoptóticas a fin de perfilar estrategias de tratamiento adecuadas para pacientes con neoplasia hepática

Role of nitric oxide increase on induced programmed cell death during early stages of rat liver regeneration.

We analysed the possible cellular mechanism involved in the NO action in the balance between apoptosis and cell proliferation in liver regeneration process. We determined p53, proapoptotic protein Bax, antiapoptotic Bcl-xL, proliferating cell nuclear antigen (PCNA) and apoptotic index at the early stages of regenerative process after NO increase by lipopolysaccharide-induction (LPS) of inducible-type nitric oxide synthase (iNOS) and by direct NO donor (sodium nitroprusside, SNP). Male Wistar rats were randomised in four experimental groups: sham operated control (Sh), partial hepatectomised control (PH-C), partial hepatectomised pretreated with LPS (2 mg/kg body weight, i.p.) (PH-LPS), and partial hepatectomised pretreated with SNP (2.5 mg/kg body weight, i.v. at a rate of 1 ml/h) (PH-SNP). Animals were killed 5 h post-surgery. Hepatic cytosolic iNOS showed an increase of 34% in PH-C animals with respect to Sh, and LPS-treatment increased iNOS protein levels 30% compared with PH-C. Bax and p53 protein levels showed significant increases in LPS- and SNP-treated hepatectomised rats with respect to PH-C. The apoptotic indexes were increased 75% in both, PH-LPS and PH-SNP rats versus PH-C. The increase of NO did not show any change in the proliferation process. These results suggest that NO is involved in apoptosis via p53 and Bax proteins after PH, showing a tightly regulated growth process in liver regeneration.

Biliary secretory function in rats chronically intoxicated with aluminum.

The effects of a chronic aluminum (Al) exposure on biliary secretory function, with special emphasis on hepatic handling of non-bile salt organic anions, was investigated. Male Wistar rats received, intraperitoneally, either 27 mg/kg body weight of Al, as Al hydroxide [Al (+) rats], or the vehicle saline [Al (-) rats] three times a week for 3 months. Serum and hepatic Al levels were increased by the treatment (approximately 9- and 4-fold, respectively). This was associated with enhanced malondialdehyde formation (+110%) and a reduction in GSH content (-17%) and in the activity of the antioxidant enzymes catalase (-84%) and GSH peroxidase (-46%). Bile flow (-23%) and the biliary output of bile salts (-39%), cholesterol (-43%), and proteins (-38%) also decreased. Compartmental analysis of the plasma decay of the model organic anion bromosulphophthalein revealed that sinusoidal uptake and canalicular excretion of the dye were significantly decreased in Al (+) rats (-53 and -43%, respectively). Expression of multidrug resistance-associated protein 2 (Mrp2), the main, multispecific transporter involved in the canalicular excretion of organic anions, was also decreased (-40%), which was associated with a significant decrease in the cumulative biliary excretion of the Mrp2 substrate, dinitrophenyl-S-glutathione (-50%). These results show that chronic Al exposure leads to oxidative stress, cholestasis, and impairment of the hepatic handling of organic anions by decreasing both sinusoidal uptake and canalicular excretion. The alteration of the latter process seems to be causally related to impairment of Mrp2 expression. We have addressed some possible mechanisms involved in these deleterious effects.

Efecto apoptótico in vivo del interferon alfa-2B (IFN) sobre hígados preneoplásicos de rata / In vivo apoptotic effect of alpha-2B interferon (IFN) on rat preneoplastic liver

Para conocer si el IFN a previene la oncogenesis in vivo, en estadíos tempranos del desarrollo tumoral, evaluamos la acción del IFN a-2b sobre focos preneoplásicos en hígado de rata. Los animales se dividieron en los siguientes grupos: sujetos a un modelo de iniciación-promoción (G1), tratados con IFN a-2b durante: a) iniciación-promoción (G2), b) iniciación (G3), c) promoción (G4); sujetos solo al estadío de iniciación (G5) y tratados con IFNa-2b en este período (G6). El área y el número de los focos preneoplásicos rGST P-positivos se mostraron significativamente disminuidos y el Indice Apoptótico aumentado en los G2, 3 y 6. Los niveles de Bcl-2 y Bcl-xL están disminuidos en los grupos tratados con IFN a-2b y los de Bax mitocondrial aumentados en los G2, 3 y 6. En conclusión, los hepatocitos preneoplásicos de ratas que recibieron IFN a-2b sufren muerte celular programada como resultado de un aumento sustancial de Bax y de su translocación a la mitocondria. (AU)

Efecto apoptótico in vivo del interferon alfa-2B (IFN) sobre hígados preneoplásicos de rata / In vivo apoptotic effect of alpha-2B interferon (IFN) on rat preneoplastic liver

Para conocer si el IFN a previene la oncogenesis in vivo, en estadíos tempranos del desarrollo tumoral, evaluamos la acción del IFN a-2b sobre focos preneoplásicos en hígado de rata. Los animales se dividieron en los siguientes grupos: sujetos a un modelo de iniciación-promoción (G1), tratados con IFN a-2b durante: a) iniciación-promoción (G2), b) iniciación (G3), c) promoción (G4); sujetos solo al estadío de iniciación (G5) y tratados con IFNa-2b en este período (G6). El área y el número de los focos preneoplásicos rGST P-positivos se mostraron significativamente disminuidos y el Indice Apoptótico aumentado en los G2, 3 y 6. Los niveles de Bcl-2 y Bcl-xL están disminuidos en los grupos tratados con IFN a-2b y los de Bax mitocondrial aumentados en los G2, 3 y 6. En conclusión, los hepatocitos preneoplásicos de ratas que recibieron IFN a-2b sufren muerte celular programada como resultado de un aumento sustancial de Bax y de su translocación a la mitocondria.

El Factor de Crecimiento Transformante beta 1 y su relación con el proceso de apoptosis durante hepatocarcinogénesis química en ratas

Estudio de los mecanismos involucrados en la apoptosis inducida por Interferón alfa-2b (IFN- 2b) de focos preneoplásicos en hígados de ratas. La caracterización de dichos mecanismos permitirá avanzar en el conocimiento de los procesos de hepatocarcinogénesis y su supresión mediante el uso de agentes inmunomoduladores con propiedades apoptóticas a fin de perfilar estrategias de tratamiento adecuadas para pacientes con neoplasia hepática