title: Docosahexaenoic acid-acylated phloridzin, a novel polyphenol fatty acid ester derivative, is cytotoxic to breast cancer cells.
abstract: Docosahexaenoic acid-acylated phloridzin (PZ-DHA), a novel polyphenol fatty acid ester derivative, was synthesized through a regioselective acylation reaction with the aim of increasing the bioactivity of phloridzin (PZ) and docosahexaenoic acid (DHA). In this study, PZ-DHA's cytotoxic activity was explored using in vitro and in vivo models of mammary carcinoma. PZ-DHA was selectively cytotoxic for mammary carcinoma (MDA-MB-231, MDA-MB-468, 4T1, MCF-7 and T-47D) cells compared to non-malignant human mammary epithelial cells (HMEC and MCF-10A) and fibroblasts by MTS assay and Annexin-V-FLUOS/propidium iodide staining. Flow cytometric analysis of Oregon Green 488- and Ki-67-stained MDA-MB-231 cells showed antiproliferative activity of PZ-DHA at a subcytotoxic concentration. PZ-DHA also arrested MDA-MB-231 cell division at the G2/M phase and down-regulated expression of cyclin B1 and cyclin-dependent kinase 1 (CDK1). PZ-DHA-induced apoptosis in MDA-MB-231 cells was confirmed by caspase 3/7 activation in a luminescence assay and DNA fragmentation by TUNEL staining. Moreover, MDA-MB-231 xenograft growth in non-obese diabetic severe combined immunodeficient mice was suppressed by intra-tumoral administration of PZ-DHA. This study shows that PZ-DHA is selectively cytotoxic to breast cancer cells in vitro and in vivo, suggesting that further investigations of PZ-DHA are warranted as a potential treatment for breast cancer.
authors.affiliation: Department of Pathology.
authors.forename: Wasundara
authors.initials: W
authors.lastname: Fernando
authors.affiliation: Department of Pathology.
authors.forename: Melanie R Power
authors.initials: MRP
authors.lastname: Coombs
authors.affiliation: Department of Pathology.|Department of Microbiology and Immunology and.|Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada and.
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
authors.affiliation: Department of Pathology.|Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia B2N 5E3, Canada.
authors.forename: H P Vasantha
authors.initials: HPV
authors.lastname: Rupasinghe
mesh_terms: D000215:Acylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016203:CDC2 Protein Kinase; D049109:Cell Proliferation / Q000187:drug effects*; D056744:Cyclin B1 / Q000096:biosynthesis* / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000008:administration & dosage; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D010695:Phlorhizin / Q000008:administration & dosage* / Q000737:chemistry; D059808:Polyphenols / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D056744:Cyclin B1; D059808:Polyphenols; D004281:Docosahexaenoic Acids; D010695:Phlorhizin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases