title: Resveratrol induces chemosensitization to 5-fluorouracil through up-regulation of intercellular junctions, Epithelial-to-mesenchymal transition and apoptosis in colorectal cancer.
abstract: 5-Fluorouracil (5-FU), a common chemotherapeutic agent used for the treatment of colorectal cancer (CRC), by itself has inadequate response rates; highlighting the need for novel and improved treatment regimens for these patients. Resveratrol, a naturally-occurring polyphenol, has been linked with chemosensitizing potential and anticancer properties; however, the underlying mechanisms for these effects remain poorly understood. The effect of resveratrol in parental CRC cell lines (HCT116, SW480) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R, SW480R) was examined by MTT assays, intercellular junction formation and apoptosis by electron- and immunoelectron microscopy, nuclear factor-kappaB (NF-κB) and NF-κB regulated gene products by western blot analysis in a 3D-alginate microenvironment. Resveratrol blocked the proliferation of all four CRC cell lines and synergized the invasion inhibitory effects of 5-FU. Interestingly, resveratrol induced a transition from 5-FU-induced formation of microvilli to a planar cell surface, which was concomitant with up-regulation of desmosomes, gap- and tight junctions (claudin-2) and adhesion molecules (E-cadherin) expression in HCT116 and HCT116R cells. Further, resveratrol significantly attenuated drug resistance through inhibition of epithelial-mesenchymal transition (EMT) factors (decreased vimentin and slug, increased E-cadherin) and down-regulation of NF-κB activation and its translocation to the nucleus and abolished NF-κB-regulated gene end-products (MMP-9, caspase-3). Moreover, this suppression was mediated through inhibition of IκBα kinase and IκBα phosphorylation and degradation. Our results demonstrate that resveratrol can potentiate the anti-tumor effects of 5-FU on CRC cells by chemosensitizing them, inhibiting an EMT phenotype via up-regulation of intercellular junctions and by down-regulation of NF-κB pathway.
authors: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany.
authors: Constanze
authors: C
authors: Buhrmann
authors: Investigating Institute of Molecular Biological System Transfer, Tehran 1417863171, Iran; Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran, 141556453, Iran.
authors: Parviz
authors: P
authors: Shayan
authors: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany.
authors: Patricia
authors: P
authors: Kraehe
authors: Department of Anatomy and Cell Biology, Biomedical Center, Ludwig-Maximilian-University Munich, D-80336 Munich, Germany.
authors: Bastian
authors: B
authors: Popper
authors: Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.
authors: Ajay
authors: A
authors: Goel
authors: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany. Electronic address: mehdi.shakibaei@med.uni-muenchen.de.
authors: Mehdi
authors: M
authors: Shakibaei
mesh_terms: D000464:Alginates; D000963:Antimetabolites / Q000008:administration & dosage / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003470:Culture Media; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects* / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000464:Alginates; D000963:Antimetabolites; D000972:Antineoplastic Agents, Phytogenic; D003470:Culture Media; D013267:Stilbenes; D000077185:Resveratrol; D005472:Fluorouracil
keywords: 5-FU; 5-Fluorouracil (5-Fluor-1H-pyrimidin-2,4-dion); Claudin-2; Colorectal cancer; E-cadherin; Junctions; Resveratrol; Resveratrol (trans-3,5,4'-Trihydroxystilben)