Source: Annual Congress 2010 - Pathology of lung cancer

Abstract

Gemcitabine (GEM) is an agent commonly used in the treatment of non small cell lung cancer (NSCLC). GEM induces apoptosis in NSCLC cells indirectly by increasing functionally active Fas expression. The aim of this study was to further explore the mechanisms involved in activation of indirect cell apoptosis. We assessed ability of GEM to upregulate expression of FasL in NSCLC cells and to increase the sensitivity of these cells to the cytotoxicity of linfokine activated killer cells (LAK) . Effects of GEM were tested on H292 (mucoepidermoid carcinoma) cell line. Cells were cultured with and without GEM (0.05 μΜ) for 24, 48, 72 and 96 hrs, and FasL mRNA and protein were evaluated by real time PCR, and by western blot and cytometry, respectively. Apoptosis of cells expressing FasL was evaluated by cytometry. Cytotoxicity of LAK against H292 cells was analyzed in presence and in absence of neutralizing anti-Fas antibody (clone ZB4), by a cytometry-based assay.
Expression of FasL mRNA and protein in H292 cells after incubation with GEM was increased at all time-points and this increase was higher after 72 hrs. Accordingly, the percentage of apoptotic H292 cells expressing FasL was higher after 72 hrs.
Cytotoxicity of LAK cells significantly increased after incubation of H292 cells with GEM and was partially inhibited by neutralizing anti-Fas antibody.
These data demonstrate that: 1) GEM induces an up-regulation of FasL in NSCLC cells, leading to an autocrine/paracrine activation of FasL signalling that may constitute a potential mechanism of anti-cancer drug-induced apoptosis; 2) GEM is able to increase the sensitivity of NSCLC cells to cytotoxic activity of LAK cells by activation of Fas/FasL system.

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L. Siena, E. Pace, M. Ferraro, C. Di Sano, M. Melis, M. Profita, M. Gjomarkaj (Palermo, Italy). Involvement of Fas/FasL system in gemcitabine-induced lung cancer cell killing. Eur Respir J 2010; 36: Suppl. 54, 3256

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