title: Natural grape extracts regulate colon cancer cells malignancy.
abstract: Natural dietary components are evolutionary-selected molecules able to control inflammation and cancerous transformation and progression. Because many studies assessed the beneficial properties of key molecules extracted from grapes, we aimed at investigating the properties of Liofenol™, a natural red wine lyophilized extract, devoid of alcohol and composed by a miscellaneous of components (polyphenols, flavonoids, anthocyanins). We proved that the colon cancer cell line HCT116 responded to Liofenol™ treatment by reducing their proliferation, in association with an increase of p53 and p21 cell cycle gate keepers. Liofenol™ increased dihydroceramides, sphingolipid mediators involved in cell cycle arrest and reduced proliferation rate. We observed a strong induction of antioxidant response, with the activation of the transcriptional factor Nrf2, involved in redox homeostasis and differentiation, without altering tumor sensitivity to chemotherapy. Liofenol™ induced an important morphology change in HCT116 cells, migration inhibition, undifferentiated stem/stem-like cells markers downregulation, and E-cadherin downregulation, interested in epithelia to mesenchymal malignant transition. We conclude that lyophilized grape extract, at dose comparable to putative dietary doses, can activate molecular pathways, involving Nrf2 signaling and the modulation of structural and signaling sphingolipid mediators that cooperate in promoting differentiation and reducing proliferation of digestive tract cancer cells.
authors.affiliation: a Department of Health Sciences , University of Milan , Milan , Italy , and San Paolo Hospital , Milan , Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Signorelli
authors.forename: Carlotta
authors.initials: C
authors.lastname: Fabiani
authors.forename: Andrea
authors.initials: A
authors.lastname: Brizzolari
authors.forename: Rita
authors.initials: R
authors.lastname: Paroni
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriàs
authors.forename: Dario
authors.initials: D
authors.lastname: Rossi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ghidoni
authors.forename: Anna
authors.initials: A
authors.lastname: Caretti
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D045325:HCT116 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D010936:Plant Extracts / Q000494:pharmacology*; D013107:Sphingolipids / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D027843:Vitis
chemical_list: D000975:Antioxidants; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010936:Plant Extracts; D013107:Sphingolipids; D016159:Tumor Suppressor Protein p53