Loss of O6-methylguanine-DNA methyltransferase confers collateral sensitivity to carmustine in topoisomerase II-mediated doxorubicin resistant triple negative breast cancer cells.

Raguz, Selina; Adams, Caroline; Masrour, Nahal; Rasul, Sabeena; Papoutsoglou, Panagiotis; Hu, Yunhui; Cazzanelli, Giulia; Zhou, Yuan; Patel, Naina; Coombes, Charles; Yagüe, Ernesto

Raguz, Selina; Adams, Caroline; Masrour, Nahal; Rasul, Sabeena; Papoutsoglou, Panagiotis; Hu, Yunhui; Cazzanelli, Giulia; Zhou, Yuan; Patel, Naina; Coombes, Charles; Yagüe, Ernesto.

Afiliación

Raguz S; Institute of Clinical Sciences, Imperial College London, London, UK. s.raguz@csc.mrc.ac.uk

Biochem Pharmacol ; 85(2): 186-96, 2013 Jan 15.

Article en En | MEDLINE | ID: mdl-23122841

RESUMEN

Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10-15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O6-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer.

Asunto(s)

Antígenos de Neoplasias/metabolismo; Antineoplásicos/farmacología; Neoplasias de la Mama/tratamiento farmacológico; Carmustina/farmacología; ADN-Topoisomerasas de Tipo II/metabolismo; Proteínas de Unión al ADN/metabolismo; Doxorrubicina/farmacología; Resistencia a Antineoplásicos/efectos de los fármacos; O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidores; Antígenos de Neoplasias/genética; Antineoplásicos/efectos adversos; Antineoplásicos/metabolismo; Transporte Biológico; Neoplasias de la Mama/metabolismo; Línea Celular Tumoral; Proliferación Celular/efectos de los fármacos; Inhibidor p21 de las Quinasas Dependientes de la Ciclina/agonistas; Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética; Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo; Metilación de ADN/efectos de los fármacos; ADN-Topoisomerasas de Tipo II/genética; Proteínas de Unión al ADN/antagonistas & inhibidores; Proteínas de Unión al ADN/genética; Doxorrubicina/efectos adversos; Doxorrubicina/metabolismo; Femenino; Fase G1/efectos de los fármacos; Regulación Neoplásica de la Expresión Génica/efectos de los fármacos; Humanos; Concentración 50 Inhibidora; Proteínas de Neoplasias/antagonistas & inhibidores; Proteínas de Neoplasias/genética; Proteínas de Neoplasias/metabolismo; O(6)-Metilguanina-ADN Metiltransferasa/genética; O(6)-Metilguanina-ADN Metiltransferasa/metabolismo; Proteínas de Unión a Poli-ADP-Ribosa; Regiones Promotoras Genéticas/efectos de los fármacos; Proteínas Recombinantes/antagonistas & inhibidores; Proteínas Recombinantes/genética; Proteínas Recombinantes/metabolismo; Inhibidores de Topoisomerasa II/farmacología; Proteína p53 Supresora de Tumor/antagonistas & inhibidores; Proteína p53 Supresora de Tumor/genética; Proteína p53 Supresora de Tumor/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Carmustina / Doxorrubicina / ADN-Topoisomerasas de Tipo II / Resistencia a Antineoplásicos / O(6)-Metilguanina-ADN Metiltransferasa / Proteínas de Unión al ADN / Antígenos de Neoplasias / Antineoplásicos Tipo de estudio: Diagnostic_studies Idioma: En Revista: Biochem Pharmacol Año: 2013 Tipo del documento: Article Pais de publicación: Reino Unido

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