RESUMEN

Although different mechanisms of acquired resistance to epidermal growth factor receptor (EGFR)­tyrosine kinase inhibitors (TKIs) have been reported in non­small cell lung cancers (NSCLCs), the optimal treatment for patients with acquired resistance has not been clearly defined. The purpose of this study was to investigate the antitumor effects of gefitinib in combination with vorinostat, a potent histone deacetylase inhibitor (HDACI), and their associated molecular mechanisms in relation to activating apoptosis in NSCLC. The treatment using a combination of vorinostat and gefitinib was more potent in promoting cell death by activating apoptosis than gefitinib alone in parental PC9 cells that harbor an EGFR­activating mutation (EGFR exon 19 deletion) and gefitinib­resistant PC9 cells (PC9GR) with an EGFR T790M mutation. This combination induced heat shock protein 90 (HSP90) cleavage and reduced the level of HSP90 client proteins, including EGFR, MET and AKT, in PC9 and PC9GR cells. The addition of 4­(2­aminoethyl) benzenesulfonyl fluoride hydrochloride, a scavenger of reactive oxygen species (ROS), inhibited the degradation of HSP90 client proteins and HSP90 cleavage that was induced by co­treatment as well as the cleavage of caspase­3, caspase­8, and caspase­9 and cell death. We also observed that cleavage of HSP90 and its clients were blocked when caspases were inhibited. These results revealed that co­treatment with vorinostat and gefitinib induced ROS­dependent caspase activation, leading to the downregulation of HSP90 clients through HSP90 cleavage. Collectively, our findings provide a new basis for strategies that combine vorinostat with an EGFR­TKI to reverse EGFR­TKI resistance in NSCLC.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Muerte Celular/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Caspasas/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/genética , Gefitinib/administración & dosificación , Humanos , Neoplasias Pulmonares/metabolismo , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , Vorinostat/administración & dosificación

RESUMEN

PURPOSE: Despite several therapeutic options renal cell carcinoma is associated with a poor clinical outcome. Therefore, we investigated whether combining 5-fluorouracil with the histone deacetylase inhibitor belinostat would exert a synergistic effect on renal cell carcinoma cells in vitro and in vivo. MATERIALS AND METHODS: We used SN12C cells treated with 5-fluorouracil and/or belinostat in vitro and in xenograft experiments in vivo. Cell viability and death mechanisms were assessed by MTS assay and Western blot. To investigate the role of reactive oxygen species we used H2DCF-DA, reactive oxygen species scavengers and the roGFP2 construct. RESULTS: Belinostat potentiated the anticancer effect of 5-fluorouracil. It synergistically induced apoptosis by activating caspases and increasing the subG1 cell population. Effects on reactive oxygen species mediated DNA damage included decreased thioredoxin expression and increased levels of TBP-2, γ-H2AX and Ac-H3. Furthermore, belinostat attenuated the 5-fluorouracil mediated induction of thymidylate synthase via HSP90 hyperacetylation. Co-administration of 5-fluorouracil with belinostat similarly reduced tumor volume and weight, and increased γ-H2AX and Ac-H3 levels in the SN12C xenograft model. CONCLUSIONS: In combination with 5-fluorouracil the targeted inhibitor of histone deacetylase synergistically inhibited renal cancer cell growth by the blockade of thymidylate synthase induction and the induction of reactive oxygen species mediated DNA damage in vitro and in vivo. Our results suggest that combined treatment with belinostat and 5-fluorouracil may represent a promising new approach to renal cancer.

Asunto(s)

Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Daño del ADN/efectos de los fármacos , Fluorouracilo/administración & dosificación , Proteínas HSP90 de Choque Térmico/efectos de los fármacos , Inhibidores de Histona Desacetilasas/administración & dosificación , Ácidos Hidroxámicos/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sulfonamidas/administración & dosificación , Timidilato Sintasa/efectos de los fármacos , Animales , Quimioterapia Combinada , Humanos , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico Sintasa , Células Tumorales Cultivadas

RESUMEN

We screened a chemical library in MCF-7 cells stably expressing green fluorescent protein (GFP)-conjugated microtubule-associated protein 1 light chain 3 (LC3) (GFP-LC3-MCF-7) using cell-based assay, and identified BIX-01294 (BIX), a selective inhibitor of euchromatic histone-lysine N-methyltransferase 2 (EHMT2), as a strong autophagy inducer. BIX enhanced formation of GFP-LC3 puncta, LC3-II, and free GFP, signifying autophagic activation. Inhibition of these phenomena with chloroquine and increasement in punctate dKeima ratio (550/438) signal indicated that BIX activated autophagic flux. BIX-induced cell death was suppressed by the autophagy inhibitor, 3-methyladenine, or siRNA against BECN1 (VPS30/ATG6), ATG5, and ATG7, but not by caspase inhibitors. Moreover, EHMT2 siRNA augmented GFP-LC3 puncta, LC3-II, free GFP, and cell death, implying that inhibition of EHMT2 caused autophagy-mediated cell death. Treatment with EHMT2 siRNA and BIX accumulated intracellular reactive oxygen species (ROS). BIX augmented mitochondrial superoxide via NADPH oxidase activation. In addition, BIX increased hydrogen peroxide and glutathione redox potential in both cytosol and mitochondria. Treatment with N-acetyl-L-cysteine (NAC) or diphenyleneiodonium chloride (DPI) decreased BIX-induced LC3-II, GFP-LC3 puncta, and cell death, indicating that ROS instigated autophagy-dependent cell death triggered by BIX. We observed that BIX potentiated autophagy-dependent and caspase-independent cell death in estrogen receptor (ESR)-negative SKBr3 and ESR-positive MCF-7 breast cancer cells, HCT116 colon cancer cells, and importantly, in primary human breast and colon cancer cells. Together, the results suggest that BIX induces autophagy-dependent cell death via EHMT2 dysfunction and intracellular ROS accumulation in breast and colon cancer cells, therefore EHMT2 inhibition can be an effective therapeutic strategy for cancer treatment.

Asunto(s)

Autofagia/efectos de los fármacos , Azepinas/farmacología , Inhibidores Enzimáticos/farmacología , Antígenos de Histocompatibilidad/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Quinazolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Células Cultivadas , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Femenino , Células HCT116 , Humanos , Células MCF-7 , Ratones , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos

RESUMEN

Previous studies have reported that a Gamitrinib variant containing triphenylphosphonium (G-TPP) binds to mitochondrial Hsp90 and rapidly inhibits its activity, thus inducing the apoptotic pathway in the cells. Accordingly, G-TPP shows a potential as a promising drug for the treatment of cancer. A cell can die from different types of cell death such as apoptosis, necrosis, necroptosis, and autophagic cell death. In this study, we further investigated the mechanisms and modes of cell death in the G-TPP-treated Hep3B and U937 cell lines. We discovered that G-TPP kills the U937 cells through the apoptotic pathway and the overexpression of Bcl-2 significantly inhibits U937 cell death to G-TPP. We further discovered that G-TPP kills the Hep3B cells by activating necroptosis in combination with the partial activation of caspase-dependent apoptosis. Importantly, G-TPP overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. We also observed that G-TPP induces compensatory autophagy in the Hep3B cell line. We further found that whereas there is a Bcl-2-Beclin 1 interaction in response to G-TPP, silencing the beclin 1 gene failed to block LC3-II accumulation in the Hep3B cells, indicating that G-TPP triggers Beclin 1-independent protective autophagy in Hep3B cells. Taken together, these data reveal that G-TPP induces cell death through a combination of death pathways, including necroptosis and apoptosis, and overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. These findings are important for the therapeutic exploitation of necroptosis as an alternative cell death program to bypass the resistance to apoptosis.

Asunto(s)

Apoptosis/fisiología , Guanidinas/administración & dosificación , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Lactamas Macrocíclicas/administración & dosificación , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos/métodos , Guanidinas/química , Humanos , Lactamas Macrocíclicas/química , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Necrosis , Células U937

RESUMEN

Fatty acid synthase (FASN) is overexpressed in a wide variety of human cancers, making it an attractive target for anticancer therapy. One of the most widely used inhibitors of FASN, cerulenin, is a natural product of Cephalosporium caerulens. Cerulenin is selectively toxic to human cancer cells in vitro. However, the mechanism by which FASN inhibition causes apoptosis in tumor cells remains unclear. Because of the widespread clinical interest in combining cerulenin with other chemotherapeutic agents, we performed this study to gain insight into the downstream effects of FASN inhibition that lead to apoptosis. Here, we observed the increased antitumor effect of cerulenin when combined with the topoisomerase inhibitor SN-38. We identified topoisomerase I as a potential mediator of cerulenin-induced apoptosis, possibly by upregulating intracellular polyunsaturation. Finally, we show that suppressing topoisomerase I catalytic activity results in synergistic effects between cerulenin and LY294002. Our results suggest that topoisomerase I could participate in cerulenin-induced apoptosis by upregulating intracellular polyunsaturation. These results will help determine the molecular basis of the cerulenin and SN-38 drug combination. Further investigation of this pathway will provide new insight into cancer cell metabolism and may aid in the design of additional cancer chemotherapeutic agents.

Asunto(s)

Apoptosis/efectos de los fármacos , Camptotecina/análogos & derivados , Cerulenina/farmacología , Ácido Graso Sintasas/antagonistas & inhibidores , Inhibidores de Topoisomerasa I/farmacología , Camptotecina/farmacología , Supervivencia Celular/efectos de los fármacos , Cromonas/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , Sinergismo Farmacológico , Ácido Graso Sintasas/metabolismo , Humanos , Irinotecán , Morfolinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Células Tumorales Cultivadas

RESUMEN

Although crystallins are major structural proteins in the lens, α-crystallins perform non-lens functions, and αB-crystallin has been shown to act as an anti-apoptotic mediator in various cells. The present study was undertaken to examine whether αB-crystallin expressed in human malignant glioma cells exerts anti-apoptotic activity. In addition, we sought to elucidate the mechanism underlying any observed anti-apoptotic function of αB-crystallin in these cells. Three glioma cell lines, U373MG, U118MG, and T98G, were used. We observed that only the U373MG cell line expresses αB-crystallin, whereas the other 2 glioma cell lines, U118MG and T98G, demonstrated no endogenous expression of αB-crystallin. We next observed that the silencing of αB-crystallin sensitized U373MG cells to suberoylanilide hydroxamic acid (SAHA)-induced apoptosis and that αB-crystallin associates with caspase-3 and XIAP. Because XIAP is the most potent suppressor of mammalian apoptosis through the direct binding with caspases, we assessed whether XIAP also plays an anti-apoptotic role in SAHA-induced apoptosis in αB-crystallin-expressing U373MG cells. Of note, the silencing of XIAP did not alter the amount of cell death induced by SAHA, indicating that XIAP does not exert an anti-apoptotic activity in U373MG cells. We then determined whether the ectopic expression of αB-crystallin in glioma cells caused a loss of the anti-apoptotic activity of XIAP. Accordingly, we established 2 αB-crystallin over-expressing glioma cell lines, U118MG and T98G, and found that the silencing of XIAP did not sensitize these cells to SAHA-induced apoptosis. These findings suggest that αB-crystallin expressed in glioma cells overrides the anti-apoptotic activity exerted by XIAP.

Asunto(s)

Apoptosis/fisiología , Glioma/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Cadena B de alfa-Cristalina/metabolismo , Western Blotting , Línea Celular Tumoral , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunoprecipitación , Microscopía Confocal , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección

RESUMEN

The Bcl-2 protein is known to exert not only anti-apoptotic but also anti-autophagic activities. Numerous studies have demonstrated that etoposide, which is one of the most widely used cancer chemotherapy agents, induces apoptotic cell death. However, the exact molecular mechanism leading to cell death by etoposide remains to be resolved. This study aimed to dissect the mode of cell death induced by etoposide in Hep3B hepatoma cells. Furthermore, this study was conducted to examine whether etoposide overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells. We observed that Hep3B cells treated with etoposide show not only apoptotic but autophagic phenotypes. Autophagy inhibition by 3-methyladenine (3MA) and caspase inhibition by zVAD-fmk effectively decreased autophagic and apoptotic phenotypes, respectively. However, either zVAD-fmk or 3MA only partially prevented cell death. These data indicate that etoposide concomitantly induces autophagic cell death and apoptosis in Hep3B cells. Importantly, etoposide can effectively induce cell death in Bcl-2-overexpressing Hep3B cells. Conversely, staurosporine, which exclusively induces apoptosis in Hep3B cells, did not efficiently induce cell death in Bcl­2­overexpressing Hep3B cells. Staurosporine-treated Hep3B cells also showed an autophagic phenotype. While autophagy is cell death-inducing in Hep3B cells treated with etoposide, it is cytoprotective in Hep3B cells treated with staurosporine. To this end, we observed that etoposide-induced mixed type of programmed cell death is associated with the dissociation of Bcl-2 from Beclin-1. Taken together, etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells.

Asunto(s)

Carcinoma Hepatocelular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Etopósido/administración & dosificación , Genes bcl-2/genética , Neoplasias Hepáticas/genética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Beclina-1 , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Inhibidores de Caspasas/farmacología , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Estaurosporina/farmacología

RESUMEN

Although various stimuli-inducing cell demise are known to alter mitochondrial morphology, it is currently debated whether alteration of mitochondrial morphology is per se responsible for apoptosis execution or prevention. This study was undertaken to examine the effect of histone deacetylase (HDAC) inhibitors on mitochondrial fusion-fission equilibrium. The mechanism underlying HDAC inhibitor-induced alteration of mitochondrial morphology was examined in various cells including primary cultured cells and untransformed and cancer cell lines treated with seven different HDAC inhibitors. Suberoylanilide hydroxamic acid (SAHA)-induced mitochondrial elongation in both Hep3B and Bcl-2-overexpressing Hep3B cells, apart from its apoptosis induction function. SAHA significantly decreased the expression of mitochondrial fission protein Fis1 and reduced the translocation of Drp1 to the mitochondria. Fis1 overexpression attenuated SAHA-induced mitochondrial elongation. In addition, depletion of mitochondrial fusion proteins, Mfn1 or Opa1, by RNA interference also attenuated SAHA-induced mitochondrial elongation. All of the HDAC inhibitors we examined induced mitochondrial elongation in all the cell types tested at both subtoxic and toxic concentrations. These results indicate that HDAC inhibitors induce mitochondrial elongation, irrespective of the induction of apoptosis, which may be linked to alterations of mitochondrial dynamics regulated by mitochondrial morphology-regulating proteins. Since mitochondria have recently emerged as attractive targets for cancer therapy, our findings that HDAC inhibitors altered mitochondrial morphology may support the rationale for these agents as novel therapeutic approaches against cancer. Further, the present study may provide insight into a valuable experimental strategy for simple manipulation of mitochondrial morphology.

Asunto(s)

Inhibidores de Histona Desacetilasas/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Acetilación/efectos de los fármacos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , División Celular/efectos de los fármacos , División Celular/genética , Línea Celular , Línea Celular Tumoral , Dinaminas , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Histonas/fisiología , Humanos , Ácidos Hidroxámicos/farmacología , Fusión de Membrana/efectos de los fármacos , Fusión de Membrana/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/enzimología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Vorinostat

RESUMEN

Since resveratrol is not a potent cytotoxic compound when compared with other chemotherapeutic agents, several previous studies have been performed to obtain synthetic analogs of resveratrol with potent activity. Our previous study demonstrated that the resveratrol analog HS-1793 showed stronger antitumor activity than resveratrol in various cancer cells. We examined the antitumor activity exerted by HS-1793 in prostate cancer cells, and we observed that HS-1793 acts as a polyploidy inducer. Noticeably, multinucleation and polyploidization were induced in most LNCaP cells treated with HS-1793 at the dose causing a slight decline in cell viability. However, the induction of multinucleation and polyploidization was much lower in PC-3 prostate cancer cells treated with the same dose of HS-1793. Western blot and RT-PCR analyses showed that the expression of Aurora B was almost undetectable in LNCaP cells, but it was highly expressed in PC-3 cells. Further, silencing of Aurora B sensitized PC-3 cells to HS-1793-induced multi-nucleation. These results indicate that expression of Aurora B determines multinucleation in prostate cancer cells treated with HS-1793. Additional assays using multiple cancer cell lines show that the population of multinucleated cells induced by HS-1793 treatment is inversely proportional to Aurora B expression. We further elicited that the HS-1793-induced polyploid LNCaP cells are vulnerable to downregulation of Bcl-xL. Since the polyploidization in LNCaP induced by HS-1793 does not appear to cause definite commitment to apoptosis, the termination of polyploid cells by inhibition of Bcl-xL could provide an advantageous means to improve chemotherapeutic efficacy of HS-1793.

Asunto(s)

Antineoplásicos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Naftoles/farmacología , Poliploidía , Resorcinoles/farmacología , Proteína bcl-X/metabolismo , Apoptosis/efectos de los fármacos , Aurora Quinasa B , Aurora Quinasas , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Células HCT116 , Humanos , Células K562 , Masculino , Neoplasias de la Próstata , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Células U937 , Proteína bcl-X/antagonistas & inhibidores

RESUMEN

BACKGROUND/AIMS: This study was designed to compare the efficacy and patient tolerance between standard bowel preparation using 4 liters of polyethylene glycol (PEG) solution and 4 liters of PEG preceded by the osmotic laxative, magnesium hydroxide in constipation and non-constipation group. METHODS: 173 outpatient colonoscopy, except for three patients who were not taking magnesium, were divided into constipation and non-constipation group. Then, the patients were randomly assigned to receive 4-liter of PEG solution or 4-liter of PEG plus magnesium hydroxide. The quality of bowel preparation was assessed using Ottawa scale, and satisfaction score was assessed using questionnaires. Solid stool, cecal intubation time, compliance, and side effects were assessed. RESULTS: Non-constipation group showed no significant differences between two groups. In constipation group, 4-liter PEG solution plus magnesium hydroxide induced the more effective colonic preparation (Ottawa scale 2.47+/-0.99 vs. 5.92+/-2.39, p<0.05), and less solid stool (0.67+/-0.72 vs. 1.38+/-0.65, p<0.05) compared with 4-liter PEG solution. CONCLUSIONS: Bowel preparation with magnesium hydroxide and 4 liters of PEG solution might reduce solid stool in constipation group, but could not improve preparation quality.

Asunto(s)

Colonoscopía , Lavado Gástrico/métodos , Hidróxido de Magnesio/administración & dosificación , Polietilenglicoles/administración & dosificación , Administración Oral , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios

RESUMEN

Bcl-2 protects cancer cells from the apoptotic effects of various chemotherapeutic agents. Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to bypass chemoresistance in cancer cells. Previously we designed and synthesized the resveratrol analogue HS-1793 displaying stronger antitumor efficacy than resveratrol and further demonstrated the HS-1793 resistance conferred by Bcl-2 in human leukemic U937 cells. We undertook this study to determine if HS-1793 treatment can bypass the anti-apoptotic effects of Bcl-2 in human renal cancer cells, with a specific focus on the involvement of promyelocytic leukemia nuclear bodies (PML-NBs). Experiments were conducted with Bcl-2-overexpressing human renal clear cell carcinoma Caki-1 cells. Various apoptosis assessment assays demonstrated that HS-1793 overcomes the resistance conferred by Bcl-2 in Caki-1 cells by inducing apoptosis. We elucidated that HS-1793-induced formation of mature promyelocytic leukemia (PML) nuclear bodies (NBs) correlates with overcoming the anti-apoptotic effects of Bcl-2 in Caki-1 cells. Our findings show that the resveratrol analogue HS-1793 might provide a novel promising strategy for overcoming the resistance conferred by Bcl-2 via PML protein and the formation of mature PML-NBs.

Asunto(s)

Antineoplásicos/farmacología , Carcinoma de Células Renales/metabolismo , Cuerpos de Inclusión Intranucleares/efectos de los fármacos , Neoplasias Renales/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Naftoles/farmacología , Resorcinoles/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Neoplasias Renales/patología , Leucemia Promielocítica Aguda/patología , Potencial de la Membrana Mitocondrial , Microscopía Confocal , Proteínas Nucleares/metabolismo , Proteína de la Leucemia Promielocítica , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Resveratrol , Estilbenos/farmacología , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo

RESUMEN

Bcl-2 protects tumor cells from the apoptotic effects of various antineoplastic agents. Increased expression of Bcl-2 has been associated with poor response to chemotherapy in various malignancies, including leukemia. Therefore, bypassing the resistance conferred by anti-apoptotic factors such as Bcl-2 represents an attractive therapeutic strategy against cancer cells, including leukemic cells. We undertook this study to examine whether SAHA (suberoylanilide hydroxamic acid) overcomes the resistance by Bcl-2 in human leukemic cells, with a specific focus on the involvement of PML-NBs. Experiments were conducted with Bcl-2-overexpressing human leukemic U937 cells. Since we previously demonstrated that overexpression of Bcl-2 attenuates resveratrol-induced apoptosis in human leukemic U937 cells, resveratrol-treated U937 cells were used as a negative control. The present study indicates that SAHA at 1-7 microM, the dose range known to induce apoptosis in various cancer cells, overcomes the anti-apoptotic effects of Bcl-2 in Bcl-2-overexpressing human leukemic U937 cells. Notably, we observed that SAHA-induced formation of mature promyelocytic leukemia (PML) nuclear bodies (NBs) correlates with overcoming the anti-apoptotic effects of Bcl-2 in human leukemic U937 cells. Thus, PML protein and the formation of mature PML-NBs could be considered as therapeutic targets that could help bypass the resistance to apoptosis conferred by Bcl-2. Elucidating exactly how PML regulates Bcl-2 will require further work.

Asunto(s)

Apoptosis/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Cuerpos de Inclusión Intranucleares/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Apoptosis/fisiología , Western Blotting , Caspasa 3/metabolismo , Electroforesis en Gel de Poliacrilamida , Técnica del Anticuerpo Fluorescente , Humanos , Leucemia/patología , Potenciales de la Membrana/efectos de los fármacos , Microscopía Confocal , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Células U937 , Vorinostat

RESUMEN

Congenital absence of the splenic artery is a very rare condition. To the best of our knowledge, congenital absence of the splenic artery accompanied with absence of the splenic vein has not been reported. We report a case of the absence of the splenic artery and vein in a 61-year-old woman who presented with postprandial epigastric discomfort. Upper gastrointestinal endoscopy showed a dilated, pulsatile vessel in the fundus and duodenal stenosis. An abdominal computed tomography (CT) scan revealed absence of the splenic vein with a tortuously engorged gastroepiploic vein. Three-dimensional CT demonstrated the tortuously dilated left gastric artery and the left gastroepiploic artery with non-visualization of the splenic artery. After administration of a proton pump inhibitor, abdominal symptoms resolved without any recurrence of symptoms during 6 mo of follow-up.

Asunto(s)

Úlcera Duodenal/patología , Arteria Esplénica/anomalías , Vena Esplénica/anomalías , 2-Piridinilmetilsulfinilbencimidazoles/uso terapéutico , Antiulcerosos/uso terapéutico , Úlcera Duodenal/diagnóstico , Úlcera Duodenal/diagnóstico por imagen , Úlcera Duodenal/tratamiento farmacológico , Duodeno/patología , Femenino , Humanos , Persona de Mediana Edad , Rabeprazol , Tomografía Computarizada por Rayos X , Resultado del Tratamiento

RESUMEN

Meckel's diverticulum is a remnant of the vitelline duct and a congenital anomaly of the gastrointestinal tract. Hemorrhage from a Meckel's diverticulum is common in children but extremely rare in adults over 50 years of age. Very few cases have been reported to date and all prior cases were in men. Meckel's diverticulum is commonly overlooked as a possible cause of a lower gastrointestinal hemorrhage in adults. Here, we present the rare case of a 58-year-old woman with massive hemorrhage from a Meckel's diverticulum that was diagnosed by repeated emergency angiographies and treated with elective laparoscopic surgery.

Asunto(s)

Angiografía , Hemorragia Gastrointestinal/diagnóstico por imagen , Divertículo Ileal/diagnóstico por imagen , Conducto Vitelino/diagnóstico por imagen , Femenino , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Humanos , Laparoscopía , Divertículo Ileal/complicaciones , Divertículo Ileal/cirugía , Persona de Mediana Edad , Conducto Vitelino/anomalías , Conducto Vitelino/cirugía