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Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations

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Abstract

The hedgehog (Hh) signaling pathway has been shown to be activated in the cancer stem cells of several tumor entities. The Hh inhibitor GDC-0449 has been proven to be effective in some cancers but not yet in lung cancer. We aimed at investigating whether GDC-0449 is effective in the lung cancer cell lines HCC (adenocarcinoma) and H1339 (small-cell-lung carcinoma), whether in these cell lines stem cell-like side populations (SPs) can be identified, and whether possible effects of GDC-0449 are mediated via SPs. SPs were identified by spectrum shift and decreased fluorescence after staining with 2.5 μg/ml Hoechst 33342. Expression of proteins was quantified by immunofluorescence. GDC-0449 (25 and 50 μM) inhibited concentration-dependent cell growth in HCC and H1339 cells. Further, the inhibitory effects of cisplatin on cell growth were augmented. In HCC and H1339 cell lines, SPs of 0.57 and 0.46% could be identified, respectively. SP, but not non-SP, cells were able to repopulate the original tumor population. The Hh receptor smoothened was detectable in SP but not in non-SP cells, showing the activation of the Hh pathway only in SPs. GDC-0449 considerably reduced SPs in HCC and H1339 cells. We demonstrate for the first time that GDC-0449 effectively reduces cell growth in lung cancer cell lines. This effect is mediated by the inhibition of stem cell-like SPs.

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Abbreviations

CSC:

Cancer stem cell

Hh:

Hedgehog

NSCLC:

Non-small cell-lung cancer

SCLC:

Small-cell-lung cancer

SMO:

Smoothened

SP:

side population

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Authors and Affiliations

  1. Division of Respiratory Medicine, Medizinische Klinik-Innenstadt, Ludwig-Maximilians-University, Ziemssenstr. 1, 80336, Munich, Germany

    Fei Tian, Fernando Gamarra, Rudolf Maria Huber & Albrecht Bergner

  2. German Research Center For Environmental Health, Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany

    Josef Mysliwietz & Joachim Ellwart

Authors
  1. Fei Tian
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  2. Josef Mysliwietz
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  3. Joachim Ellwart
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  4. Fernando Gamarra
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  5. Rudolf Maria Huber
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  6. Albrecht Bergner
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Correspondence to Albrecht Bergner.

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Tian, F., Mysliwietz, J., Ellwart, J. et al. Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clin Exp Med 12, 25–30 (2012). https://doi.org/10.1007/s10238-011-0135-8

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  • DOI: https://doi.org/10.1007/s10238-011-0135-8

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