title: Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling.
abstract: OBJECTIVE
  Emerging evidence suggests that highly treatment-resistant tumour-initiating cells (TICs) play a central role in the pathogenesis of pancreatic cancer. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered to be 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 nuclear factor-kappaB (NF-kappaB) signalling. Several chemopreventive agents are able to inhibit NF-kappaB, and favourable results have been obtained--for example, for the broccoli compound sulforaphane-in preventing metastasis in clinical studies. The aim of the study was to identify TICs in pancreatic carcinoma for analysis of resistance mechanisms and for definition of sensitising 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, aldehyde dehydrogenase (ALDH) activity and therapy resistance.
  
  
  RESULTS
  Mechanistically, specific binding of transcriptionally active cRel-containing NF-kappaB complexes in TICs was observed. Sulforaphane prevented NF-kappaB binding, downregulated apoptosis inhibitors and induced apoptosis, together with prevention of clonogenicity. Gemcitabine, the chemopreventive agents resveratrol and wogonin, and the death ligand TRAIL were less effective. In a xenograft model, sulforaphane strongly blocked tumour growth and angiogenesis, while combination with TRAIL had an additive effect without obvious cytotoxicity in normal cells. Freshly isolated patient tumour cells expressing markers for TICs could be sensitised by sulforaphane for TRAIL-induced cytotoxicity.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Molecular OncoSurgery Group, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Kallifatidis
authors.forename: V
authors.initials: V
authors.lastname: Rausch
authors.forename: B
authors.initials: B
authors.lastname: Baumann
authors.forename: A
authors.initials: A
authors.lastname: Apel
authors.forename: B M
authors.initials: BM
authors.lastname: Beckermann
authors.forename: A
authors.initials: A
authors.lastname: Groth
authors.forename: J
authors.initials: J
authors.lastname: Mattern
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Kolb
authors.forename: G
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: P
authors.initials: P
authors.lastname: Altevogt
authors.forename: T
authors.initials: T
authors.lastname: Wirth
authors.forename: J
authors.initials: J
authors.lastname: Werner
authors.forename: P
authors.initials: P
authors.lastname: Schemmer
authors.forename: M W
authors.initials: MW
authors.lastname: Büchler
authors.forename: A V
authors.initials: AV
authors.lastname: Salnikov
authors.forename: I
authors.initials: I
authors.lastname: Herr
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017879:Isothiocyanates; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D013861:Thiocyanates / Q000627:therapeutic use*
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D016328:NF-kappa B; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand; D013861:Thiocyanates; C016766:sulforaphane