Clinical and Experimental Medicine

, Volume 12, Issue 1, pp 25–30

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

  • Fei Tian
  • Josef Mysliwietz
  • Joachim Ellwart
  • Fernando Gamarra
  • Rudolf Maria Huber
  • Albrecht Bergner
Original Article

DOI: 10.1007/s10238-011-0135-8

Cite this article as:
Tian, F., Mysliwietz, J., Ellwart, J. et al. Clin Exp Med (2012) 12: 25. doi:10.1007/s10238-011-0135-8

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.

Keywords

GDC-0449Lung cancerStem cellSide populationHedgehog

Abbreviation

CSC

Cancer stem cell

Hh

Hedgehog

NSCLC

Non-small cell-lung cancer

SCLC

Small-cell-lung cancer

SMO

Smoothened

SP

side population

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Fei Tian
    • 1
  • Josef Mysliwietz
    • 2
  • Joachim Ellwart
    • 2
  • Fernando Gamarra
    • 1
  • Rudolf Maria Huber
    • 1
  • Albrecht Bergner
    • 1
  1. 1.Division of Respiratory Medicine, Medizinische Klinik-InnenstadtLudwig-Maximilians-UniversityMunichGermany
  2. 2.German Research Center For Environmental HealthInstitute of Molecular Immunology, Helmholtz Zentrum MünchenMunichGermany