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Sulforaphane targets pancreatic tumor-initiating cells by NF-κB-induced anti-apoptotic signaling
  1. Georgios Kallifatidis (g.kallifatidis{at}dkfz.de)
  1. University of Heidelberg, General Surgery, Germany
    1. Vanessa Rausch (vanessa.rausch{at}gmx.net)
    1. University of Heidelberg, General Surgery, Germany
      1. Bernd Baumann (bernd.baumann{at}uni-ulm.de)
      1. University of Ulm, Physiological Chemistry, Germany
        1. Anja Apel (anja.apel{at}uni-heidelberg.de)
        1. University of Heidelberg, General Surgery, Germany
          1. Benjamin M Beckermann (b.beckermann{at}dkfz.de)
          1. University of Heidelberg, Experimental Surgery, Molecular OncoSurgery, Germany
            1. Ariane Groth (ariane.groth{at}uni-heidelberg.de)
            1. University of Heidelberg, Experimental Surgery, Molecular OncoSurgery, Germany
              1. Jürgen Mattern (j.mattern{at}dkfz.de)
              1. University of Heidelberg, General Surgery, Germany
                1. Zhanqing Li (zhanqingli2006{at}yahoo.com)
                1. University of Heidelberg, General Surgery, Germany
                  1. Armin Kolb (armin.kolb{at}med.uni-heidelberg.de)
                  1. University of Heidelberg, General Surgery, Germany
                    1. Gerhard Moldenhauer (g.moldenhauer{at}dkfz.de)
                    1. German Cancer Research Center, Molecular Immunology, Germany
                      1. Peter Altevogt (p.altevogt{at}med.uni-heidelberg.de)
                      1. German Cancer Research Center, Tumour Immunology Programme, Germany
                        1. Thomas Wirth (thomas.wirth{at}uni-ulm.de)
                        1. University of Ulm, Physiological Chemistry, Germany
                          1. Jens Werner (jens.werner{at}med.uni-heidelberg.de)
                          1. University of Heidelberg, General Surgery, Germany
                            1. Peter Schemmer (peter.schemmer{at}med.uni-heidelberg.de)
                            1. University of Heidelberg, General Surgery, Germany
                              1. Markus W. Büchler (markus.buechler{at}med.uni-heidelberg.de)
                              1. University of Heidelberg, General Surgery, Germany
                                1. Alexei V. Salnikov (a.salnikov{at}dkfz.de)
                                1. German Cancer Research Center, Molecular Immunology, Germany
                                  1. Ingrid Herr (i.herr{at}dkfz.de)
                                  1. University of Heidelberg, General Surgery, Germany

                                    Abstract

                                    Background Emerging evidence suggests that highly therapy resistant tumor-initiating cells (TICs) play a central role in the pathogenesis of pancreatic cancer. TRAIL is taken into account as a novel anticancer agent, however, recent studies have shown that many pancreatic cancer cells are resistant to apoptosis induction by TRAIL due to TRAIL-activated NF-κB signaling. Several chemopreventive agents are able to inhibit NF-κB and favourable results have been obtained e.g. for broccoli compound sulforaphane in preventing metastasis in clinical studies.

                                    Aims We aimed to identify TICs in pancreatic carcinoma for analysis of resistance mechanisms and for definition of sensitizing agents.

                                    Methods TICs were defined by expression patterns of a CD44+/CD24-, CD44+/CD24+ or CD44+/CD133+ phenotype and correlation to growth in immunodeficient mice, differentiation grade, clonogenic growth, sphere formation, ALDH activity, and therapy resistance.

                                    Results Mechanistically, we observed specific binding of transcriptionally active cRel-containing NF-κB complexes in TICs. Sulforaphane prevented NF-κB binding, downregulated apoptosis inhibitors and induced apoptosis along with prevention of clonogenicity. Gemcitabine, the chemopreventive agents resveratrol and wogonin, or the death ligand TRAIL were less effective. In a xenograft model, sulforaphane strongly blocked tumor growth and angiogenesis while combination with TRAIL had an additive effect without obvious cytotoxicity on normal cells. Freshly isolated patient tumor cells expressing markers for TICs could be sensitized by sulforaphane for TRAIL-induced cytotoxity.

                                    Conclusion Our data provide new insights into resistance mechanisms of TICs and suggest the combination of sulforaphane with TRAIL as a promising strategy for targeting of pancreatic TICs.

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