Dietary polyphenol quercetin targets pancreatic cancer stem cells.
According to the cancer stem cell hypothesis the aggressive growth and early metastasis of pancreatic cancer may arise through dysregulation of self-renewal of stem cells in the tissue. Since recent data suggest targeting of cancer stem cells by some dietary agents we studied the effect of quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Using in vitro and in vivo models of pancreatic cancer stem cells we found quercetin-mediated reduction of self-renewal as measured by spheroid and colony formation. Quercetin diminished ALDH1 activity and reverted apoptosis resistance as detected by substrate assays, FACS and Western blot analysis. Importantly, combination of quercetin with sulforaphane, an isothiocyanate enriched in broccoli, had synergistic effects. Although quercetin led to enhanced binding of the survival factor NF-kappaB, co-incubation with sulforaphane completely eliminated this pro-proliferative feature. Moreover, quercetin prevented expression of proteins involved in the epithelial-mesenchymal transition, which was even stronger in presence of sulforaphane, suggesting the blockade of signaling involved in early metastasis. In vivo, quercetin inhibited growth of cancer stem cell-enriched xenografts associated with reduced proliferation, angiogenesis, cancer stem cell-marker expression and induction of apoptosis. Co-incubation with sulforaphane increased these effects and no pronounced toxicity on normal cells or mice was observed. Our data suggest that food ingredients complement each other in the elimination of cancer stem cell-characteristics. Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities may be most effective.
Zhou
Wei
W
Molecular OncoSurgery, University Hospital Heidelberg and German Cancer Research Center Heidelberg, Heidelberg, Germany.
Kallifatidis
Georgios
G
Baumann
Bernd
B
Rausch
Vanessa
V
Mattern
Jürgen
J
Gladkich
Jury
J
Giese
Nathalia
N
Moldenhauer
Gerhard
G
Wirth
Thomas
T
Büchler
Markus W
MW
Salnikov
Alexei V
AV
Herr
Ingrid
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017879:Isothiocyanates; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011794:Quercetin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D011794:Quercetin; C016766:sulforaphane