Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells.

Mir, Roser; Tortosa, Avelina; Martinez-Soler, Fina; Vidal, August; Condom, Enric; Pérez-Perarnau, Alba; Ruiz-Larroya, Tatiana; Gil, Joan; Giménez-Bonafé, Pepita

Mir, Roser; Tortosa, Avelina; Martinez-Soler, Fina; Vidal, August; Condom, Enric; Pérez-Perarnau, Alba; Ruiz-Larroya, Tatiana; Gil, Joan; Giménez-Bonafé, Pepita.

Afiliación

Mir R; Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.

Int J Cancer ; 132(7): 1525-36, 2013 Apr 01.

Article en En | MEDLINE | ID: mdl-22961628

RESUMEN

Ovarian cancer (OVCa) is the leading cause of death from gynecological malignancies. Although treatment for advanced OVCa has improved with the introduction of taxane-platinum chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the causes of chemoresistance is the reduced ability to undergo apoptosis. Cisplatin is a genotoxic drug that leads cells to apoptosis through the activation of the p53 pathway. Defective signaling in this pathway compromises p53 function, and thus cisplatin does not induce apoptosis. A new group of nongenotoxic small molecules called Nutlins have been developed to inhibit p53-Mdm2 binding, inducing apoptosis in chemoresistant tumors through the activation of the p53 pathway. The wild-type p53 cisplatin-resistant ovarian cancer cell-line A2780cis was used to test the effect of Nutlin-3a (Nut3a) on apoptosis response. The results showed that Nut3a synergized with cisplatin, inducing cell-cycle arrest in G2/M and potentiating apoptotic cell death. Increased apoptosis was also induced in wild-type TP53 primary OVCa cultures by double cisplatin-Nut3a treatment. In conclusion, Nut3a appears to sensitize chemoresistant OVCa cells to cisplatin, inducing apoptosis. As increased response was generalized in primary tumors, this cisplatin-Nut3a combination could be useful for the treatment of patients harboring wild-type TP53 who do not respond to standard chemotherapy.

Asunto(s)

Apoptosis/efectos de los fármacos; Cisplatino/farmacología; Resistencia a Antineoplásicos/efectos de los fármacos; Imidazoles/farmacología; Neoplasias Ováricas/patología; Piperazinas/farmacología; Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores; Proteína p53 Supresora de Tumor/metabolismo; Adenocarcinoma Mucinoso/tratamiento farmacológico; Adenocarcinoma Mucinoso/metabolismo; Adenocarcinoma Mucinoso/patología; Antineoplásicos/farmacología; Western Blotting; Ciclo Celular/efectos de los fármacos; Proliferación Celular/efectos de los fármacos; Cistadenocarcinoma Seroso/tratamiento farmacológico; Cistadenocarcinoma Seroso/metabolismo; Cistadenocarcinoma Seroso/patología; Sinergismo Farmacológico; Neoplasias Endometriales/tratamiento farmacológico; Neoplasias Endometriales/metabolismo; Neoplasias Endometriales/patología; Femenino; Citometría de Flujo; Humanos; Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores; Proteínas Inhibidoras de la Apoptosis/genética; Proteínas Inhibidoras de la Apoptosis/metabolismo; Clasificación del Tumor; Neoplasias Ováricas/tratamiento farmacológico; Neoplasias Ováricas/metabolismo; ARN Mensajero/genética; ARN Interferente Pequeño/genética; Reacción en Cadena en Tiempo Real de la Polimerasa; Reacción en Cadena de la Polimerasa de Transcriptasa Inversa; Survivin; Células Tumorales Cultivadas; Proteína p53 Supresora de Tumor/antagonistas & inhibidores; Proteína p53 Supresora de Tumor/genética

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Piperazinas / Proteína p53 Supresora de Tumor / Cisplatino / Apoptosis / Resistencia a Antineoplásicos / Proteínas Proto-Oncogénicas c-mdm2 / Imidazoles Tipo de estudio: Prognostic_studies Idioma: En Revista: Int J Cancer Año: 2013 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos

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