RESUMEN
Myxoid Liposarcomas (MLS), characterized by the expression of FUS-CHOP fusion gene are clinically very sensitive to the DNA binding antitumor agent, trabectedin. However, resistance eventually occurs, preventing disease eradication. To investigate the mechanisms of resistance, a trabectedin resistant cell line, 402-91/ET, was developed. The resistance to trabectedin was not related to the expression of MDR related proteins, uptake/efflux of trabectedin or GSH levels that were similar in parental and resistant cells. The 402-91/ET cells were hypersensitive to UV light because of a nucleotide excision repair defect: XPG complementation decreased sensitivity to UV rays, but only partially to trabectedin. 402-91/ET cells showed collateral sensitivity to temozolomide due to the lack of O(6) -methylguanine-DNA-methyltransferase (MGMT) activity, related to the hypermethylation of MGMT promoter. In 402-91 cells chromatin immunoprecipitation (ChIP) assays showed that FUS-CHOP was bound to the PTX3 and FN1 gene promoters, as previously described, and trabectedin caused FUS-CHOP detachment from DNA. Here we report that, in contrast, in 402-91/ET cells, FUS-CHOP was not bound to these promoters. Differences in the modulation of transcription of genes involved in different pathways including signal transduction, apoptosis and stress response between the two cell lines were found. Trabectedin activates the transcription of genes involved in the adipogenic-program such as c/EBPα and ß, in 402-91 but not in 402-91/ET cell lines. The collateral sensitivity of 402-91/ET to temozolomide provides the rationale to investigate the potential use of methylating agents in MLS patients resistant to trabectedin.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Línea Celular Tumoral , Dioxoles/farmacología , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/metabolismo , Tetrahidroisoquinolinas/farmacología , Apoptosis , Proteína C-Reactiva/genética , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/genética , Metilación de ADN , Metilasas de Modificación del ADN/deficiencia , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Reparación del ADN , Enzimas Reparadoras del ADN/deficiencia , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Resistencia a Antineoplásicos , Fibronectinas/genética , Humanos , Liposarcoma Mixoide/tratamiento farmacológico , Liposarcoma Mixoide/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Regiones Promotoras Genéticas , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Componente Amiloide P Sérico/genética , Transducción de Señal , Temozolomida , Trabectedina , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Rayos UltravioletaRESUMEN
We provide an overview of the available information on the distribution of chemotherapeutics in human tumors, highlighting the progress made to assess the heterogeneity of drug concentrations in relation to the complex neoplastic tissue using novel analytical methods, e.g., mass spectrometry imaging. The increase in interstitial fluid pressure due to abnormal vascularization and stiffness of tumor stroma explains the variable and heterogeneous drug concentrations. Therapeutic strategies to enhance tumor drug distribution, thus possibly increasing efficacy, are discussed.