title: Pterostilbine, an active component of blueberries, sensitizes colon cancer cells to 5-fluorouracil cytotoxicity.
abstract: Although colorectal cancer (CRC) treatment with 5-fluorouracil (5-FU) is the first line of therapy for this debilitating disease, treatment effectiveness is often hampered by the development of drug resistance and toxicity at high doses. ER-β can play an important role in CRC development and possibly in its response to therapy. Pterostilbene (PT) possesses antioxidant and anticancer effects that are mediated by ER-β. In the current study, we test the hypothesis that PT sensitizes colon cancer cells to 5-FU and we examine the underlying mechanism(s) by which PT exerts its cytotoxic effects in CRC cells. Our data indicate that PT exhibited a more potent cytotoxic effect in Caco-2 compared to HCT-116 cells. PT/5-FU co-treatment was more effective in Caco-2 cells. Our data indicate that ER-β is expressed at higher levels in Caco-2 cells and its levels are further boosted with PT treatment. PT significantly suppressed Akt and ERK phosphorylations, and enhanced FOXO-1 and p27(kip1) levels in Caco-2 cells. PT also induced a significant increase in Caco-2 cells at pre-G phase coupled with increased Bax/Bcl-2 ratio and PARP cleavage. These results provide a rationale for novel combination treatment strategies, especially for patients with 5-FU-resistant tumors expressing ER-β protein.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.|Biology Department, School of Sciences and Engineering, The American University in Cairo, New Cairo, Egypt.
authors.forename: Mai F
authors.initials: MF
authors.lastname: Tolba
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas, Medical Branch, Galveston 77555, USA.
authors.forename: Sherif Z
authors.initials: SZ
authors.lastname: Abdel-Rahman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D029798:Blueberry Plants / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D020134:Catalytic Domain; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004357:Drug Synergism; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047629:Estrogen Receptor beta; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D013267:Stilbenes; D050760:Cyclin-Dependent Kinase Inhibitor p27; C107773:pterostilbene; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005472:Fluorouracil