Many anticancer drugs exert their cytotoxicity through DNA damage and induction of apoptosis. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) have di erent sensitivity to treatment with radiation and chemotherapeutic agents with SCLC being more sensitive than NSCLC both in vitro and in vivo. This di erence might be related to the di erent susceptibility of small and non-small cell lung carcinoma to undergo apoptosis. The aim of this study was to investigate if de®ciencies in the apoptotic pathways can explain the intrinsic resistance of NSCLC to anti-cancer treatment. Three di erent triggers were used to induce apoptosis. Etoposide and g-radiation, which are important parts of clinical lung cancer treatment, induce DNA-damage, whereas Fas ligation induces receptormediated apoptotic pathways. NSCLC cells were crossresistant to all treatments, whereas SCLC cells, which do not express pro-caspase-8, were resistant to aFas-, but not to DNA-damage-induced apoptosis. Cytochrome c release, activation of caspase-9 and the executioner caspase-3 were observed in both types of lung cancer cells. However, cleavage of known nuclear substrates for caspase-3, such as PARP and DFF45/ICAD, was documented only in the sensitive SCLC cells but not in the resistant NSCLC cells. Moreover, relocalization of active caspase-3 from the cytosol into the nucleus upon treatment was observed only in the SCLC cell line. These results indicate that the inhibition of apoptosis in NSCLC occurs downstream of mitochondrial changes and caspase activation, and upstream of nuclear events.

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