Sulforaphane Increases Drug-mediated Cytotoxicity Toward Cancer Stem-like Cells of Pancreas and Prostate

• Published in: Molecular therapy Vol. 19; no. 1; pp. 188 - 195
• Main Authors: Kallifatidis, Georgios, Labsch, Sabrina, Rausch, Vanessa, Mattern, Juergen, Gladkich, Jury, Moldenhauer, Gerhard, Büchler, Markus W., Salnikov, Alexei V., Herr, Ingrid
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2011; Elsevier Limited; Nature Publishing Group
• Subjects: Aldehyde Dehydrogenase - antagonists & inhibitors; Aldehyde Dehydrogenase - metabolism; Aldehyde Dehydrogenase 1 Family; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Brassica; Cancer research; Cancer therapies; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Dehydrogenases; Drug dosages; Drug Synergism; Female; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Isothiocyanates; Male; Medical research; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Original; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-rel - antagonists & inhibitors; Proto-Oncogene Proteins c-rel - metabolism; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - genetics; Retinal Dehydrogenase; Spheroids, Cellular; Stem cells; Surgery; Thiocyanates - pharmacology; Toxicity; Tumor Stem Cell Assay - methods; Germany
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2010.216

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 drugs—as 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.