title: Sulforaphane synergizes with quercetin to inhibit self-renewal capacity of pancreatic cancer stem cells.
abstract: According to the cancer stem cell hypothesis, the aggressive growth and early metastasis of cancer may arise through dysregulation of self-renewal of stem cells. The objectives of this study were to examine the molecular mechanisms by which sulforaphane (SFN, an active compound in cruciferous vegetables) inhibits self-renewal capacity of pancreatic cancer stem cells (CSCs), and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Our data demonstrated that SFN inhibited self-renewal capacity of pancreatic CSCs. Inhibition of Nanog by lentiviral-mediated shRNA expression enhanced the inhibitory effects of sulforaphane on self-renewal capacity of CSCs. SFN induced apoptosis by inhibiting the expression of Bcl-2 and XIAP, phosphorylation of FKHR, and activating caspase-3. Moreover, SFN inhibited expression of proteins involved in the epithelial-mesenchymal transition (beta-catenin, vimentin, twist-1, and ZEB1), suggesting the blockade of signaling involved in early metastasis. Furthermore, the combination of quercetin with SFN had synergistic effects on self-renewal capacity of pancreatic CSCs. These data suggest that SFN either alone or in combination with quercetin can eliminate cancer stem cell-characteristics.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, USA. rsrivastava@kumc.edu
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Srivastava
authors.forename: Su-Ni
authors.initials: SN
authors.lastname: Tang
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhu
authors.forename: Daniel
authors.initials: D
authors.lastname: Meeker
authors.forename: Sharmila
authors.initials: S
authors.lastname: Shankar
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005822:Genetic Vectors / Q000235:genetics; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D017879:Isothiocyanates; D016086:Lentivirus; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D017879:Isothiocyanates; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013454:Sulfoxides; D013861:Thiocyanates; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D011794:Quercetin; C016766:sulforaphane