TY - JOUR
T1 - Sulforaphane increases drug-mediated cytotoxicity toward cancer stem-like cells of pancreas and prostate
AU - Kallifatidis, Georgios
AU - Labsch, Sabrina
AU - Rausch, Vanessa
AU - Mattern, Juergen
AU - Gladkich, Jury
AU - Moldenhauer, Gerhard
AU - Büchler, Markus W.
AU - Salnikov, Alexei V.
AU - Herr, Ingrid
N1 - Funding Information:
This study was supported by grants from the Bundesministerium für Bildung und Forschung (01GU0611), Tumorzentrum Heidelberg/Mannheim (D10027(6)350), Stiftung Chirurgie Heidelberg, Dietmar-Hopp Stiftung and Deutsche Krebshilfe. All authors disclose any commercial affiliations or consultancies, stock or equity interests, or patent-licensing arrangements that could be considered to pose a financial conflict of interest related to the submitted manuscript.
PY - 2011/1
Y1 - 2011/1
N2 - Despite intense efforts to develop treatments against pancreatic cancer, agents that cure this highly resistant and metastasizing disease are not available. Considerable attention has focused on broccoli compound sulforaphane (SF), which is suggested as combination therapy for targeting of pancreatic cancer stem cells (CSCs). However, there are concerns that antioxidative properties of SF may interfere with cytotoxic drugsas suggested, e.g., for vitamins. Therefore we investigated a combination therapy using established pancreatic CSCs. Although cisplatin (CIS), gemcitabine (GEM), doxorubicin, 5-flurouracil, or SF effectively induced apoptosis and prevented viability, combination of a drug with SF increased toxicity. Similarly, SF potentiated the drug effect in established prostate CSCs revealing that SF enhances drug cytotoxicity also in other tumor entities. Most importantly, combined treatment intensified inhibition of clonogenicity and spheroid formation and aldehyde dehydrogenase 1 (ALDH1) activity along with Notch-1 and c-Rel expression indicating that CSC characteristics are targeted. In vivo, combination treatment was most effective and totally abolished growth of CSC xenografts and tumor-initiating potential. No pronounced side effects were observed in normal cells or mice. Our data suggest that SF increases the effectiveness of various cytotoxic drugs against CSCs without inducing additional toxicity in mice.
AB - Despite intense efforts to develop treatments against pancreatic cancer, agents that cure this highly resistant and metastasizing disease are not available. Considerable attention has focused on broccoli compound sulforaphane (SF), which is suggested as combination therapy for targeting of pancreatic cancer stem cells (CSCs). However, there are concerns that antioxidative properties of SF may interfere with cytotoxic drugsas suggested, e.g., for vitamins. Therefore we investigated a combination therapy using established pancreatic CSCs. Although cisplatin (CIS), gemcitabine (GEM), doxorubicin, 5-flurouracil, or SF effectively induced apoptosis and prevented viability, combination of a drug with SF increased toxicity. Similarly, SF potentiated the drug effect in established prostate CSCs revealing that SF enhances drug cytotoxicity also in other tumor entities. Most importantly, combined treatment intensified inhibition of clonogenicity and spheroid formation and aldehyde dehydrogenase 1 (ALDH1) activity along with Notch-1 and c-Rel expression indicating that CSC characteristics are targeted. In vivo, combination treatment was most effective and totally abolished growth of CSC xenografts and tumor-initiating potential. No pronounced side effects were observed in normal cells or mice. Our data suggest that SF increases the effectiveness of various cytotoxic drugs against CSCs without inducing additional toxicity in mice.
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U2 - 10.1038/mt.2010.216
DO - 10.1038/mt.2010.216
M3 - Article
C2 - 20940707
AN - SCOPUS:78650901935
SN - 1525-0016
VL - 19
SP - 188
EP - 195
JO - Molecular Therapy
JF - Molecular Therapy
IS - 1
ER -