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1.
J Biol Chem ; 287(32): 26495-505, 2012 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-22718761

RESUMEN

Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform ΔNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response.


Asunto(s)
Apoptosis/fisiología , Carcinoma Embrionario/patología , Cisplatino/farmacología , Proteínas de Unión al ADN/fisiología , Regulación Neoplásica de la Expresión Génica/fisiología , Proteínas Nucleares/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factor de Transcripción Sp1/fisiología , Neoplasias Testiculares/patología , Proteínas Supresoras de Tumor/fisiología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Secuencia de Bases , Carcinoma Embrionario/tratamiento farmacológico , Carcinoma Embrionario/genética , Línea Celular Tumoral , Cisplatino/uso terapéutico , Estudios de Cohortes , Cartilla de ADN , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Pronóstico , Regiones Promotoras Genéticas , Reacción en Cadena en Tiempo Real de la Polimerasa , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/genética , Proteína Tumoral p73
2.
Oncotarget ; 6(22): 18875-90, 2015 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-26056084

RESUMEN

Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Dioxoles/farmacología , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Sarcoma de Ewing/tratamiento farmacológico , Tetrahidroisoquinolinas/farmacología , Animales , Línea Celular Tumoral , Niño , Daño del ADN , Dioxoles/administración & dosificación , Sinergismo Farmacológico , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Distribución Aleatoria , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Tetrahidroisoquinolinas/administración & dosificación , Trabectedina , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Clin Cancer Res ; 20(6): 1542-54, 2014 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-24486586

RESUMEN

PURPOSE: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models. EXPERIMENTAL DESIGN: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. RESULTS: Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-κB ligand)-induced NF-κB activation, F-actin ring disruption, and diminished expression of αVß3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/ß-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow-disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). CONCLUSION: Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma.


Asunto(s)
Compuestos de Boro/farmacología , Glicina/análogos & derivados , Mieloma Múltiple/metabolismo , Osteoclastos/efectos de los fármacos , Inhibidores de Proteasoma/farmacología , Animales , Antineoplásicos/farmacología , Resorción Ósea/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Glicina/farmacología , Humanos , Immunoblotting , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Osteoclastos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
Clin Sarcoma Res ; 3(1): 3, 2013 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-23497641

RESUMEN

BACKGROUND: The systemic treatment of malignant endometrial stromal tumors (EST) is not well established. A few reports describe objective responses to imatinib, which suggest a novel therapeutic strategy for these tumors. Due to these facts, we aimed to perform a retrospective analysis of possible molecular targets of tyrosine kinase inhibitors (TKI) in EST: KIT, PDGFRA and EGFR. METHODS: 52 endometrial stromal sarcomas and 13 undifferentiated endometrial sarcomas were examined and reviewed. Mutational analysis were performed for exons 9, 11, 13, and 17 of the KIT gene, exons 12 and 18 of the PDGFRA gene and exons 18, 19, 20 and 21 of the EGFR gene. The incidence and distribution of the KIT, PDGFRA, and EGFR expression were examined by immunohistochemistry, and EGFR amplification was assessed by fluorescence in situ hybridization. RESULTS: No mutations in KIT, PDGFRA and EGFR genes were detected. Overexpression of KIT, PDGFRA, EGFR, was detected in 2 (3%), 23 (35.4%), 7 (10.8%) cases respectively, whereas amplification of EGFR gene was not found. CONCLUSIONS: Absence of significant expression, amplification and activating mutations on these tyrosine kinase receptors suggest that it is unlikely that EST can benefit from therapies such as TKI on the systemic setting.

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