strong inverse correlation between Bcl-xL expression and gemcitabine-induced apoptosis in pancreatic

Discussion in 'Health and medical' started by Roger, Feb 16, 2004.

  1. Roger

    Roger Guest

    This implies substances that inhibit Bcl-xL expression will make pancreatic cancer cells more
    vulnerable to gemcitabine.
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    Int J Cancer. 2004 Mar 20;109(2):182-8.

    Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated
    apoptosis.

    Schniewind B, Christgen M, Kurdow R, Haye S, Kremer B, Kalthoff H, Ungefroren H. Clinic for General
    and Thoracic Surgery, Molecular Oncology Research Group, University of Kiel, Germany.

    Palliative chemotherapy with gemcitabine, a common mode of treatment of pancreatic cancer, has
    little influence on patients' survival. We investigated the impact of anti-apoptotic Bcl-xL protein
    and its antagonist Bax on gemcitabine-induced apoptosis in human pancreatic carcinoma cells in
    vitro and in vivo. The level of Bcl-xL and Bax expression was determined in 3 established
    pancreatic cancer cell lines that differ in their sensitivity to gemcitabine-mediated apoptosis.
    Bcl-xL and Bax genes were transduced into Colo357 cells by retroviral infection. In addition, cells
    were transfected with c-FLIP to assess involvement of CD95 and caspase-8. The impact of Bax/Bcl-xL
    expression on gemcitabine-sensitivity in vivo was evaluated in orthotopic Colo357 tumors in SCID
    mice. The apoptotic index revealed a strong inverse correlation between Bcl-xL expression and gemcitabine-
    induced apoptosis in the pancreatic carcinoma cell lines tested. Caspase-8 and Bid were cleaved in
    Colo357 cells exposed to gemcitabine, and there was no correlation with either Bcl-xL or with Bax
    expression. In contrast, the lack of mitochondrial transmembrane potential transition, release of
    cytochrome-c and absence of caspase-9- and PARP-cleavage showed a strong correlation with Bcl-xL
    expression. Expression of c-FLIP significantly increased the resistance towards gemcitabine.
    Orthotopically growing Colo357-bcl-xl tumors in SCID mice were refractory to gemcitabine treatment,
    and in contrast to the in vitro data, Colo357-bax tumors exhibited a 12-fold greater tumor
    regression than Colo357-wild-type tumors in the control group. Gemcitabine-induced apoptosis
    involves the mitochondria-mediated signaling pathway. A functional restoration of this pathway
    appears to be essential to overcome the resistance mechanisms of pancreatic tumor cells and to
    improve the response to therapy as demonstrated by Bax overexpression in a clinically relevant
    tumor model.
     
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