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1.
Food Funct ; 13(1): 316-326, 2022 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-34897340

RESUMEN

Maritime pine bark is a rich source of polyphenolic compounds and is commonly employed as a herbal supplement worldwide. This study was designed to check the potential of maritime pine tannin extract (MPTE) in anticancer therapy and to determine the underlying mechanism of action. Our results showed that MPTE, containing procyanidin oligomers and lanostane type terpenoids, has an inhibitory effect on cancer cell proliferation through cell cycle arrest in the G2/M phase. Treatment with MPTE also induced apoptosis in a concentration-dependent manner in human cancer cell lines (HeLa and U2OS), as evidenced by the enhanced activation of caspase 3 and the cleavage of PARP along with the downregulation of the antiapoptotic protein Bcl-2. Interestingly, human non-cancerous fibroblasts are much less sensitive to MPTE, suggesting that it preferentially targets cancer cells. MPTE played a pro-oxidant role in cancer cells and promoted the expression of the p73 tumor suppressor gene in p53-deficient cells. It also downregulated the protooncogenic proteins UHRF1 and DNMT1, mediators of the DNA methylation machinery, and reduced the global methylation levels in HeLa cells. Overall, our results show that maritime pine tannin extract can play a favorable role in cancer treatment, and can be further explored by the pharmaceutical industry.


Asunto(s)
Antineoplásicos/farmacología , Proteínas Potenciadoras de Unión a CCAAT , Epigénesis Genética/efectos de los fármacos , Pinus/química , Taninos/farmacología , Ubiquitina-Proteína Ligasas , Apoptosis/efectos de los fármacos , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células HeLa , Humanos , Corteza de la Planta/química , Extractos Vegetales/farmacología , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
2.
Cancer Med ; 8(5): 2449-2461, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30972950

RESUMEN

BACKGROUND: Vitamin D3 (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer (BCa). In addition to cystectomy, patients are treated with cisplatin-based chemotherapy, however 30%-50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown. METHODS: To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D3 (1,25D3 ). Lastly, using BCa cell lines, T24 and RT-112, the mechanism of action of 1,25D3 and cisplatin combination treatment was determined by apoptosis assays, as well as western blot and RT-PCR. RESULTS: In this study, we determined that low serum 25 hydroxyvitamin D3 (25D3 ) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D3 , reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D3 pretreatment increased the apoptotic response to cisplatin. 1,25D3 pretreatment increased expression of TAp73 and its pro-apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D3 treatment and further increased after the combination of 1,25D3 and cisplatin in a TAp73 dependent manner. CONCLUSIONS: Our data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TAp73 signaling crosstalk.


Asunto(s)
Colecalciferol/farmacología , Cisplatino/farmacología , Receptores de Calcitriol/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína Tumoral p73/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Modelos Biológicos , Pronóstico , Receptores de Calcitriol/genética , Proteína Tumoral p73/genética , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/mortalidad , Deficiencia de Vitamina D/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Phytomedicine ; 55: 179-190, 2019 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-30668428

RESUMEN

BACKGROUND: Epithelial-to-mesenchymal transition (EMT), a key step in oral cancer progression, is associated with invasion, metastasis, and therapy resistance, thus targeting the EMT represents a critical therapeutic strategy for the treatment of oral cancer metastasis. Our previous study showed that Abrus agglutinin (AGG), a plant lectin, induces both intrinsic and extrinsic apoptosis to activate the tumor inhibitory mechanism. OBJECTIVE: This study aimed to investigate the role of AGG in modulating invasiveness and stemness through EMT inhibition for the development of antineoplastic agents against oral cancer. METHODS: The EMT- and stemness-related proteins were studied in oral cancer cells using Western blot analysis and fluorescence microscopy. The potential mechanisms of Snail downregulation through p73 activation in FaDu cells were evaluated using Western blot analysis, immunoprecipitation, confocal microscopy, and molecular docking analysis. Immunohistochemical staining of the tumor samples of AGG-treated FaDu-xenografted nude mice was performed. RESULTS: At the molecular level, AGG-induced p73 suppressed Snail expression, leading to EMT inhibition in FaDu cells. Notably, AGG promoted the translocation of Snail from the nucleus to the cytoplasm in FaDu cells and triggered its degradation through ubiquitination. In this setting, AGG inhibited the interaction between Snail and p73 in FaDu cells, resulting in p73 activation and EMT inhibition. Moreover, in epidermal growth factor (EGF)-stimulated FaDu cells, AGG abolished the upregulation of extracellular signal-regulated kinase (ERK)1/2 that plays a pivotal role in the upregulation of Snail to regulate the EMT phenotypes. In immunohistochemistry analysis, FaDu xenografts from AGG-treated mice showed decreased expression of Snail, SOX2, and vimentin and increased expression of p73 and E-cadherin compared with the control group, confirming EMT inhibition as part of its anticancer efficacy against oral cancer. CONCLUSION: In summary, AGG stimulates p73 in restricting EGF-induced EMT, invasiveness, and stemness by inhibiting the ERK/Snail pathway to facilitate the development of alternative therapeutics for oral cancer.


Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias de la Boca/tratamiento farmacológico , Lectinas de Plantas/farmacología , Factores de Transcripción de la Familia Snail/metabolismo , Proteína Tumoral p73/metabolismo , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Factor de Crecimiento Epidérmico/metabolismo , Humanos , Ratones Desnudos , Simulación del Acoplamiento Molecular , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Lectinas de Plantas/química , Factores de Transcripción de la Familia Snail/química , Factores de Transcripción de la Familia Snail/genética , Proteína Tumoral p73/química , Proteína Tumoral p73/genética , Ubiquitinación , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Food Funct ; 8(11): 4062-4069, 2017 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-28976514

RESUMEN

Grape pomace is a rich source of phenolic compounds commonly employed for elaboration of dietary supplements. The aim of the present study was to investigate the anticancer effect of a purified white grape pomace extract (PWGPE) in acute lymphoblastic leukemia Jurkat cells and to characterize the underlying mechanism. Apoptosis, mitochondrial membrane potential and reactive oxygen species (ROS) levels were assessed by flow cytometry and protein expression levels were analysed by Western blotting. PWGPE induced apoptosis in Jurkat cells in a time- and concentration-dependent manner. The anticancer effect was associated with an increased expression of p73 and down-regulation of pro-survival factors, including p-Akt, Bcl-2, and survivin. PWGPE reduced the expression of several proteins that block the expression of apoptosis-related genes such as DNMT1, HDAC1/2, UHRF1, and the polycomb group protein members: EZH2, SUZ12, and BMI1. In addition, the extract induced the formation of ROS, whereas pre-treatment with PEG-catalase and N-acetylcysteine prevented the ROS formation and markedly decreased the induction of apoptosis. These findings suggest that PWGPE-induced apoptosis in Jurkat human leukemia cells, is mediated by mitochondrial depolarization and caspase-3 cleavage, and depends on ROS generation and regulation of epigenetic gene silencing. Therefore, PWGPE may play an important role in the treatment of acute lymphoblastic leukemia (ALL).


Asunto(s)
Apoptosis/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Fenoles/farmacología , Extractos Vegetales/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Vitis/química , Caspasa 3/genética , Caspasa 3/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Humanos , Células Jurkat , Fenoles/análisis , Extractos Vegetales/análisis , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo
5.
Genes Dev ; 31(17): 1738-1753, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28971956

RESUMEN

Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.


Asunto(s)
Neoplasias Cerebelosas/dietoterapia , Neoplasias Cerebelosas/fisiopatología , Glutamina/metabolismo , Meduloblastoma/dietoterapia , Meduloblastoma/fisiopatología , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Glutaminasa/genética , Glutaminasa/metabolismo , Xenoinjertos , Humanos , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análisis de Supervivencia , Serina-Treonina Quinasas TOR/metabolismo , Resultado del Tratamiento , Células Tumorales Cultivadas
6.
Cereb Cortex ; 27(5): 2841-2856, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-27178193

RESUMEN

A unique population of cells, called "lot cells," circumscribes the path of the lateral olfactory tract (LOT) in the rodent brain and acts to restrict its position at the lateral margin of the telencephalon. Lot cells were believed to originate in the dorsal pallium (DP). We show that Lhx2 null mice that lack a DP show a significant increase in the number of mGluR1/lot cells in the piriform cortex, indicating a non-DP origin of these cells. Since lot cells present common developmental features with Cajal-Retzius (CR) cells, we analyzed Wnt3a- and Dbx1-reporter mouse lines and found that mGluR1/lot cells are not generated in the cortical hem, ventral pallium, or septum, the best characterized sources of CR cells. Finally, we identified a novel origin for the lot cells by combining in utero electroporation assays and histochemical characterization. We show that mGluR1/lot cells are specifically generated in the lateral thalamic eminence and that they express mitral cell markers, although a minority of them express ΔNp73 instead. We conclude that most mGluR1/lot cells are prospective mitral cells migrating to the accessory olfactory bulb (OB), whereas mGluR1+, ΔNp73+ cells are CR cells that migrate through the LOT to the piriform cortex and the OB.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica/fisiología , Receptores de Glutamato Metabotrópico/metabolismo , Células Madre/fisiología , Tálamo/citología , Tálamo/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Embrión de Mamíferos , Femenino , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Proteínas con Homeodominio LIM/genética , Proteínas con Homeodominio LIM/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis/fisiología , Embarazo , Receptores de Glutamato Metabotrópico/genética , Proteínas de Dominio T Box/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo
7.
Mol Med Rep ; 14(4): 3955-60, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27599791

RESUMEN

Triple-negative breast cancer (TNBC) is a breast cancer subtype that has an aggressive phenotype, is highly metastatic, has limited treatment options and is associated with a poor prognosis. In addition, metastatic TNBC has no preferred standard chemotherapy due to resistance to anthracyclines and taxanes. The present study demonstrated that a herbal extract, SH003, reduced cell viability and induced apoptosis in TNBC without cell cytotoxicity. Cell viability was examined using trypan blue exclusion and colony formation assays, which revealed a decrease in the cell viability. Additionally, apoptosis was determined using flow cytometry and a sub­G1 assay, which revealed an increase in the proportion of cells in the sub­G1 phase. The present study investigated the anticancer effect of SH003 in the Hs578T, MDA­MB­231 and ZR­751 TNBC cell lines, and in the MCF7 and T47D non­TNBC cell lines. Western blot analysis revealed that the expression levels of poly­ADP­ribose polymerase (PARP) cleavage protein in cells treated with SH003 were increased dose­dependent manner, indicating that SH003 induced apoptosis via a caspase­dependent pathway. Pre­treatment with the caspase inhibitor Z­VAD reduced SH003­induced apoptosis was examined using trypan blue exclusion. Moreover, SH003 treatment enhanced the p73 levels in MDA­MB­231 cells but not in MCF7 cells. Transfection of p73 small interfering RNA (siRNA) in MDA­MB0231 cells revealed that the apoptotic cell death induced by SH003 was significantly impaired in comparison with scramble siRNA transfected MDA­MB­231 cells. This was examined using trypan blue exclusion and flow cytometry analysis (sub­G1). In addition, SH003 and paclitaxel exhibited synergistic anticancer effects on TNBC cells. The results indicate that SH003 exerts its anticancer effect via p73 protein induction and exhibits synergistic anticancer effects when combined with paclitaxel.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Extractos Vegetales/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Proteína Tumoral p73/metabolismo , Angelica , Planta del Astrágalo , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Paclitaxel/farmacología , Trichosanthes , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
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