Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells.

PURPOSE

The aim of this study was to investigate the expression and biological activity of aromatase (CYP19A1) in malignant mesothelioma (MM).

EXPERIMENTAL DESIGN

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).

CONCLUSION

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.