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    Characterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents.

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    Authors
    Uboldi, S
    Bernasconi, S
    Romano, M
    Marchini, S
    Fuso Nerini, I
    Damia, G
    Ganzinelli, M
    Marangon, E
    Sala, F
    Clivio, L
    Chiorino, G
    Di Giandomenico, S
    Rocchi, M
    Capozzi, O
    Margison, Geoffrey P
    Watson, Amanda J
    Caccuri, A M
    Pastore, A
    Fossati, A
    Mantovani, R
    Grosso, F
    Tercero, J C
    Erba, E
    D'Incalci, M
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    Affiliation
    Department of Oncology, Mario Negri Institute, Via La Masa 19, 20156 Milan, Italy.
    Issue Date
    2012-07-01
    
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    Abstract
    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 β, 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.
    Citation
    Characterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents. 2012, 131 (1):59-69 Int J Cancer
    Journal
    International Journal of Cancer
    URI
    http://hdl.handle.net/10541/251615
    DOI
    10.1002/ijc.26340
    PubMed ID
    21805478
    Type
    Article
    Language
    en
    ISSN
    1097-0215
    ae974a485f413a2113503eed53cd6c53
    10.1002/ijc.26340
    Scopus Count
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    All Paterson Institute for Cancer Research

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