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Neuronal differentiation by indomethacin and IBMX inhibits proliferation of small cell lung cancer cells in vitro.
MedLine Citation:
PMID:  21511354     Owner:  NLM     Status:  Publisher    
BACKGROUND: Small cell lung cancer (SCLC) is one of the most aggressive malignancies implying a very poor prognosis for patients even under therapy. Since it is known that SCLC cells exhibit neurone-like characteristics, we investigated whether a neuronal induction medium (NID) consisting of indomethacin (200μM), 3-isobutyl-1-methylxanthine (IBMX, 500μM) and insulin (5μg/ml) induces neuronal differentiation and by this reduces malignancy of SCLC in vitro. METHODS: Anti-proliferative effects were tested by incubating five SCLC cell lines (OH1, OH3, SW2, H69 and H82) with NID for 72h (XTT-assay). Afterwards, anti-proliferative as well as cytotoxic effects (lactate dehydrogenase [LDH] assay, electron microscopy) of a range of drug concentrations (indomethacin 6.25-800μM, IBMX 15.625-2000μM and combinations of both) regarding H82 and SW2 were analysed. We further investigated the presence of cyclooxygenase- (COX-) 1 and 2 (IHC, Western blot) as well as levels of COX-2 before and after treatment. Neuronal differentiation was evaluated by morphological analyses (electron microscopy), detection of CD 56 and CD 171 (FACS) and recording Na(+) and K(+) currents (patch clamp). RESULTS: Proliferation of all cell lines was inhibited significantly in a dose dependent manner (linear regression), whereas SW2 and H82 were most sensitive. Treatment with insulin alone had no effect at all. Cytotoxic effects were only observed after incubation with high concentrations of indomethacin (H82) and combined treatment (SW2). COX-1 and 2 were detectable in H82 and SW2, whereas the level of COX-2 remained unaffected under treatment. By electron microscopy, we could not observe distinct neurone-like morphological changes after 72h of treatment. However, the majority of H82 and SW2 cells expressed both CD 56 (NCAM) and CD 171 (L1), showing an increase of NCAM and L1 intensity at the cell surface after 7 and 14 days of treatment. We further demonstrated an up-regulation of neurone-specific Na(+) currents as well as a significant down-regulation of herg K(+) currents after NID treatment. CONCLUSION: Our findings demonstrate significant anti-proliferative, non-toxic effects of indomethacin and IBMX on SCLC cells in vitro. Treated SCLC cells further possess increased neuronal characteristics in vitro, possibly leading to a reduced malignant potential.
Annika Lange; Heike Gustke; Günter Glassmeier; Markus Heine; Uwe Zangemeister-Wittke; Jürgen R Schwarz; Udo Schumacher; Tobias Lange
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-19
Journal Detail:
Title:  Lung cancer (Amsterdam, Netherlands)     Volume:  -     ISSN:  1872-8332     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8800805     Medline TA:  Lung Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Institute of Anatomy II: Experimental Morphology and University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
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