RESUMEN
Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Indoles/farmacología , Maleimidas/farmacología , Neuroblastoma/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Indoles/administración & dosificación , Irinotecán/administración & dosificación , Irinotecán/farmacología , Maleimidas/administración & dosificación , Ratones , Ratones Desnudos , Neuroblastoma/enzimología , Neuroblastoma/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation.
Asunto(s)
Biomimética/métodos , Lipoproteínas HDL/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Nanopartículas del Metal/uso terapéutico , Animales , Anexina A5 , Apoptosis/fisiología , Western Blotting , Fluoresceína-5-Isotiocianato , Humanos , Immunoblotting , Células Jurkat , Lipoproteínas HDL/metabolismo , Espectrometría de Masas , Ratones , Microscopía Electrónica de Transmisión , Receptores Depuradores de Clase B/metabolismoRESUMEN
We investigated a prognostic significance and the mechanism of aberrant nuclear expression of EZH2, a histone methyltransferase, in human renal cell carcinoma (RCC). We found nuclear EZH2 in 48 of 100 RCCs and it was significantly correlated with worse survival in RCC patients. We detected a decreased expression of miR-101 in 15 of 54 RCCs. We found that re-expression of miR-101 resulted in EZH2 depletion and decreased renal cancer cell proliferation. Our results show nuclear EZH2 as a prognostic marker of worse survival in human RCC, and identify miR-101 as a negative regulator of EZH2 expression and renal cancer cell proliferation.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Proteínas de Unión al ADN/genética , Elementos de Facilitación Genéticos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , MicroARNs/metabolismo , Factores de Transcripción/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/mortalidad , Núcleo Celular/metabolismo , Proliferación Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/mortalidad , Masculino , MicroARNs/genética , Persona de Mediana Edad , Complejo Represivo Polycomb 2 , Interferencia de ARN , Factores de Transcripción/metabolismo , Células Tumorales CultivadasRESUMEN
Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales/enzimología , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias Renales/enzimología , Ratones , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Sorafenib , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Stem cells were suggested to be present in human prostate cancer as a small population of distinct cells, which may contribute to carcinogenesis, tumor recurrence, and chemoresistance. To identify potential prostatic stem cells, we analyzed the expression of several potential stem cell markers in benign prostate and prostatic adenocarcinoma. METHODS: CD44, CD133, Oct4, SOX2, and EZH2 expression was detected by immunohistochemical (IHC) staining using tissue microarray assays (TMA) composed of benign (non-neoplastic) prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and prostatic adenocarcinoma. Positive staining was defined as 1+ (<10%), 2+ (10-50%), or 3+ (>50%). RESULTS: We found CD44 staining in 97% and 72% of benign + HGPIN and malignant lesions, respectively. CD133 staining was detected in a small fraction (4 of 67) of prostate carcinomas. We found that Oct4 nuclear expression was strongly associated with benign lesions and HGPIN but not prostate cancer (P < 0.05). In most cases, nuclear expression of EZH2 and SOX2 was detected in less than 10% of cells in non-neoplastic prostate glands, HGPINs or prostate adenocarcinomas. Moreover, 27 of 33 SOX2 1+ prostate cancers were also EZH2 1+, whereas all 33 of these cases were CD44+. CONCLUSIONS: Expression of CD44 and Oct4 identified large populations of benign and malignant cells in the prostate, which did not fit the definition of stem cells as a small fraction of the total cell population. Our results suggest that combined expression of embryonic stem cell markers EZH2 and SOX2 might identify potential cancer stem cells as a minor (<10%) subgroup in CD44+ prostatic adenocarcinoma.
Asunto(s)
Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Células Madre Neoplásicas/metabolismo , Próstata/metabolismo , Neoplasia Intraepitelial Prostática/metabolismo , Neoplasias de la Próstata/metabolismo , Antígeno AC133 , Adenocarcinoma/patología , Antígenos CD/análisis , Antígenos CD/metabolismo , Biomarcadores de Tumor/análisis , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Glicoproteínas/análisis , Glicoproteínas/metabolismo , Humanos , Receptores de Hialuranos/análisis , Receptores de Hialuranos/metabolismo , Masculino , Células Madre Neoplásicas/patología , Factor 3 de Transcripción de Unión a Octámeros/análisis , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Péptidos/análisis , Péptidos/metabolismo , Complejo Represivo Polycomb 2 , Próstata/patología , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/patología , Factores de Transcripción SOXB1/análisis , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción/análisis , Factores de Transcripción/metabolismoRESUMEN
Glycogen Synthase Kinase-3ß (GSK-3ß), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. The objective of the present study was to evaluate aberrant expression of GSK-3ß as a potential biomarker in human breast and head and neck cancers. Nuclear/cytosolic fractionation, immunoblotting and immunohistochemical staining was used to study the expression of GSK-3ß in human breast and head and neck cancer. Aberrant nuclear accumulation of GSK-3ß in five human breast cancer cell lines was demonstrated and in 89/128 (70%) human breast carcinomas, whereas no detectable expression of GSK-3ß was found in benign breast tissue. Nuclear GSK-3ß expression was associated with HER-2 positive tumors (P=0.02) and non-triple negative breast carcinomas (P=0.0001), although nuclear GSK-3ß was observed in some samples across all breast cancer subtypes. Aberrant nuclear expression of GSK-3ß was found in 11/15 (73%) squamous cell head and neck carcinomas, whereas weak or no detectable expression of GSK-3ß was found in benign salivary gland and other benign head and neck tissues. These results support the hypothesis that aberrant nuclear GSK-3ß may represent a potential target for the clinical treatment of human breast and squamous cell carcinoma.