title: Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells.
abstract: Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs.
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Labsch
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bauer
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Yiyao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Ewa
authors.initials: E
authors.lastname: Aleksandrowicz
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Jury
authors.initials: J
authors.lastname: Gladkich
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schönsiegel
authors.affiliation: Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004357:Drug Synergism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D017346:Protein Serine-Threonine Kinases; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand; D000097782:NF-kappaB-Inducing Kinase; C016766:sulforaphane