title: Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition.
abstract: Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all malignancies, and current therapeutic options do not target cancer stem cells (CSCs), which may be the reason for the extreme aggressiveness. The dietary agents sulforaphane and quercetin enriched e.g., in broccoli, and the main and best studied green tea catechin EGCG hold promise as anti-CSC agents in PDA. We examined the efficacy of additional catechins and the combination of these bioactive agents to stem cell features and miRNA signaling. Two established and one primary PDA cell line and non-malignant pancreatic ductal cells were used. Whereas each agent strongly inhibited colony formation, the catechins ECG and CG were more effective than EGCG. A mixture of green tea catechins (GTCs) significantly inhibited viability, migration, expression of MMP-2 and -9, ALDH1 activity, colony and spheroid formation and induced apoptosis, but the combination of GTCs with sulforaphane or quercetin was superior. Following treatment with bioactive agents, the expression of miR-let7-a was specifically induced in cancer cells but not in normal cells and it was associated with K-ras inhibition. These data demonstrate that sulforaphane, quercetin and GTC complement each other in inhibition of PDA progression by induction of miR-let7-a and inhibition of K-ras.
authors.affiliation: Molecular Oncosurgery, University Clinic of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Appari
authors.affiliation: Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Kamesh R
authors.initials: KR
authors.lastname: Babu
authors.affiliation: Molecular Oncosurgery, University Clinic of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Kaczorowski
authors.affiliation: Molecular Oncosurgery, University Clinic of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gross
authors.affiliation: Molecular Oncosurgery, University Clinic of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011794:Quercetin / Q000494:pharmacology*; D013454:Sulfoxides; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; C117307:KRAS protein, human; D035683:MicroRNAs; D010936:Plant Extracts; D011518:Proto-Oncogene Proteins; D013454:Sulfoxides; C487931:mirnlet7 microRNA, human; D002392:Catechin; D011794:Quercetin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C016766:sulforaphane