title: Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells.
abstract: OBJECTIVE
  The aim of this study was to investigate the expression and biological activity of aromatase (CYP19A1) in malignant mesothelioma (MM).
  
  
  METHODS
  We found CYP19A1 in five human MM cell lines using reverse transcription polymerase chain reaction and Western immunoblots and in a group of samples from patients with MM by immunohistochemistry. Aromatization activity was determined in MM cells by enzyme-linked immunosorbent assay as a measure of estradiol (E2) product, in basal condition and after addition of cytokine, prostaglandin-E2, and epidermal growth factor to MM cells. Treatment of MM cells with exemestane, a CYP19A1 inhibitor, was assessed by cell proliferation kit, cell cycle analysis, and Western blot for caspase, poly(ADP-ribose)polymerase, Bcl-xL, and v-akt murin thymoma viral oncogene homolog (Akt).
  
  
  RESULTS
  Biological activity of CYP19A1, already present in basal condition, was increased in MPP89 and Ist-Mes1 cells after treatment with cytokine, in all MM cells on prostaglandin-E2 treatment, and in MPP89, Ist-Mes2, and Ist-Mes1 after addition of epidermal growth factor. Treatment of MM cells with exemestane led to significant reduction of tumor cell growth, perturbation of cell cycle, caspase activation, poly(ADP-ribose)polymerase cleavage, and down-regulation of phosphorylation of Akt and Bcl-xL. In tumor tissues, we found a cytoplasmic localization of CYP19A1. By univariate analysis, overall survival resulted to be strongly influenced by high CYP19A1 expression (p = 0.001).
  
  
  CONCLUSIONS
  These findings show that CYP19A1 is present in MM and that cell growth can be down-regulated by exemestane. As Akt pathway and Bcl-xL are implicated in conferring resistance to conventional chemotherapy, exemestane could open new treatment strategies to be associated with standard therapy for patients afflicted with MM.
authors.affiliation: Department for the Development of Therapeutic Programs, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stoppoloni
authors.forename: Luisa
authors.initials: L
authors.lastname: Salvatori
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Paola
authors.initials: P
authors.lastname: Muti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Verdina
authors.forename: Ada
authors.initials: A
authors.lastname: Sacchi
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.forename: Rossella
authors.initials: R
authors.lastname: Galati
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D001141:Aromatase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008654:Mesothelioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D001141:Aromatase; C056516:exemestane