title: Additive enhancement of apoptosis by TRAIL and fenretinide in metastatic breast cancer cells in vitro.
abstract: Successful management of metastatic breast cancer still needs better chemotherapeutic approaches. The combination of fenretinide (4-HPR), a synthetic retinoid inducing apoptosis by ROS generation, and TRAIL, a cell death ligand inducing caspase-dependent apoptosis, might result in more powerful cytotoxic activity. We therefore investigated the cytotoxic activity and resulting cell death mode of this combination in MDA-MB-231 cell line as a representative of metastatic state. Cytotoxicity was assessed by the ATP viability assay while the mode of cell death was determined both morphologically using fluorescence microscopy and biochemically using Western blotting and ELISA. The combination resulted in an additive cytotoxic effect at the doses used. Fragmented and/or pyknotic nuclei, which is a feature of apoptosis, were observed after treatment with fenretinide or TRAIL. However, the combinatorial treatment further increased apoptotic figures. Confirming apoptosis, active caspase-3 and cleaved PARP were increased by fenretinide or TRAIL in both western blotting and ELISA. Again, apoptosis was further increased by the combination. The combination warrants further studies due to its superior cytotoxic activity in the metastatic setting of breast cancer.
authors.affiliation: Uludag University, Faculty of Medicine, Department of Medical Biochemistry, Bursa, Turkey. Electronic address: eulukaya@uludag.edu.tr.
authors.forename: Engin
authors.initials: E
authors.lastname: Ulukaya
authors.affiliation: Uludag University, Faculty of Arts and Sciences, Department of Biology, Bursa, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Sarimahmut
authors.affiliation: Uludag University, Faculty of Arts and Sciences, Department of Biology, Bursa, Turkey.
authors.forename: Buse
authors.initials: B
authors.lastname: Cevatemre
authors.affiliation: Uludag University, Faculty of Arts and Sciences, Department of Biology, Bursa, Turkey.
authors.forename: Ferda
authors.initials: F
authors.lastname: Ari
authors.affiliation: Dumlupinar University, Faculty of Medicine, Department of Medical Biology, Kütahya, Turkey.
authors.forename: Azmi
authors.initials: A
authors.lastname: Yerlikaya
authors.affiliation: University of Thessaly, School of Medicine, Department of Pharmacology, Biopolis, Larissa, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Dimas
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage; D006801:Humans; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; D017313:Fenretinide; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3
keywords: Breast cancer; Chemotherapy; Cytotoxicity; Fenretinide; TRAIL