title: Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro.
abstract: Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment.
authors.affiliation: Radiation Oncology; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Marvaso
authors.affiliation: Radiation Oncology; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Barone
authors.affiliation: Medical Oncology Unit; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Medical Oncology Unit; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Raimondi
authors.affiliation: Laboratory of Molecular Oncology; Magna Graecia University of Catanzaro; Catanzaro, Italy; CIS for Genomics and Molecular Pathology; Department of Experimental and Clinical Medicine; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Agosti
authors.affiliation: Medical Oncology Unit; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Altomare
authors.affiliation: Malzoni Radiosurgery Center; Agropoli; Salerno, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Scotti
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology; Second University of Naples; Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Lombardi
authors.affiliation: Department of Molecular and Clinical Endocrinology and Oncology; Biomorphological and Functional Sciences; University "Federico II" of Naples; Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.affiliation: Radiation Oncology; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Cataldo
authors.initials: C
authors.lastname: Bianco
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology; Second University of Naples; Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.affiliation: Medical Oncology Unit; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Medical Oncology Unit; Magna Graecia University of Catanzaro and T. Campanella Cancer Center; Catanzaro, Italy.
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001943:Breast Neoplasms; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D011409:Propylene Glycols / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D011409:Propylene Glycols; D011838:Radiation-Sensitizing Agents; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Akt; Erk; FTY720; apoptosis; autophagy; breast cancer; radiation therapy; sphingosine