TY - JOUR
T1 - Dietary polyphenol quercetin targets pancreatic cancer stem cells
AU - Zhou, Wei
AU - Kallifatidis, Georgios
AU - Baumann, Bernd
AU - Rausch, Vanessa
AU - Mattern, Jürgen
AU - Gladkich, Jury
AU - Giese, Nathalia
AU - Moldenhauer, Gerhard
AU - Wirth, Thomas
AU - Büchler, Markus W.
AU - Salnikov, Alexei V.
AU - Herr, Ingrid
PY - 2010/9
Y1 - 2010/9
N2 - 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-κB, 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.
AB - 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-κB, 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.
KW - Cancer stem cells
KW - Chemopreventive agents
KW - Pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=77956543290&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956543290&partnerID=8YFLogxK
U2 - 10.3892/ijo-00000704
DO - 10.3892/ijo-00000704
M3 - Article
C2 - 20664924
AN - SCOPUS:77956543290
SN - 1019-6439
VL - 37
SP - 551
EP - 561
JO - International journal of oncology
JF - International journal of oncology
IS - 3
ER -