title: Cyclooxygenase-2 inhibitors reverse chemoresistance phenotype in medullary thyroid carcinoma by a permeability glycoprotein-mediated mechanism.
abstract: OBJECTIVE
  Medullary thyroid carcinoma (MTC) is a highly chemoresistant malignant neoplasia deriving from parafollicular C cells. Chemotherapy failure has been ascribed, at least in part, to the overexpression by MTC of the multidrug resistance 1 (MDR1) gene, encoding a transmembrane glycoprotein [permeability glycoprotein (P-gp)] that antagonizes intracellular accumulation of cytotoxic agents. P-gp expression and function in a rat model have been demonstrated to depend on cyclooxygenase (COX)-2 isoform levels, which are found elevated in many human cancers. The aim of our study was to investigate the role of the COX-2 pathway in modulating chemoresistance.
  
  
  RESULTS
  We investigated P-gp and COX-2 expression and then evaluated the sensitizing effects of COX-2 inhibitors on the cytotoxic effects of doxorubicin in the presence or in the absence of prostaglandin E2 in primary cultures and in a human MTC cell line, TT. Moreover, P-gp function has been studied. Our data show that TT cells express both MDR1 and COX-2 and that rofecoxib, a selective COX-2 inhibitor, sensitizes TT cells to the cytotoxic effects of doxorubicin, reducing P-gp expression and function.
  
  
  CONCLUSIONS
  Our data suggest that these effects are mediated by a mechanism not involving the generation of prostaglandin E2, possibly implicating the synthesis of other COX-2 products.
authors.affiliation: Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Luchin
authors.forename: Daniela
authors.initials: D
authors.lastname: Piccin
authors.forename: Federico
authors.initials: F
authors.lastname: Tagliati
authors.forename: Arianna
authors.initials: A
authors.lastname: Bottoni
authors.forename: Cristina
authors.initials: C
authors.lastname: Vignali
authors.forename: Marta
authors.initials: M
authors.lastname: Bondanelli
authors.forename: Ettore C
authors.initials: EC
authors.lastname: degli Uberti
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000378:metabolism*; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008565:Membrane Proteins; D010539:Permeability; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D008565:Membrane Proteins; D012334:RNA, Neoplasm; D013450:Sulfones; C116926:rofecoxib; D004317:Doxorubicin; D014700:Verapamil; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone