Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells

Our plain-English summary of Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells, by D. Stoppoloni, L. Salvatori, A. Biroccio, et al (Journal of Thoracic Oncology, 2011).

The study

• Authors: D. Stoppoloni, L. Salvatori, A. Biroccio, C. D'Angelo, P. Muti, A. Verdina, A. Sacchi, B. Vincenzi, A. Baldi, R. Galati
• Journal: Journal of Thoracic Oncology
• Published: 2011;6(3):583-91
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This laboratory study tested whether malignant mesothelioma cells make aromatase (CYP19A1), an estrogen-producing enzyme, and whether the aromatase-blocking drug exemestane slows their growth. It also examined tumor samples from 29 patients treated in Naples between 1980 and 1996. Asbestos exposure was not studied. Aromatase was found in all five mesothelioma cell lines tested. Its activity rose with prostaglandin-E2 in all five lines and with epidermal growth factor in three. In three cell lines, exemestane reduced cell growth, disturbed the cell cycle and produced signs of cell death. It also lowered Bcl-xL. Phosphorylated Akt fell in Ist-Mes1 and MPP89, while Ist-Mes2 had none detectable before treatment. In the tumor samples, aromatase staining was either negative or found in the cell cytoplasm. In a univariate analysis, patients with high aromatase expression had shorter median survival than those with low or absent expression. The authors concluded that aromatase is present in mesothelioma and that exemestane can reduce cell growth. They stated that the patient data were retrospective and observational and came from a small number of heterogeneously treated patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of human malignant mesothelioma cell lines, combined with a retrospective review of archived patient tumor specimens stained for aromatase
• Who was studied: Five human malignant mesothelioma cell lines (NCI-H2452, MPP89, Ist-Mes1, Ist-Mes2, MSTO-211H), with the breast cancer cell line MCF-7 as a comparison. Also 29 mesothelioma tumor specimens (16 epithelioid, six sarcomatoid, seven biphasic) from patients treated at the Second University of Naples, Italy, between 1980 and 1996.
• Exposure: No asbestos exposure was studied. The cells were treated with the aromatase inhibitor exemestane over a range of concentrations for 48 hours. The concentration figures are damaged in the text. Aromatase activity was also tested after adding testosterone, prostaglandin-E2, epidermal growth factor, or a cytokine mixture.
• Main results:
  • Aromatase (CYP19A1) protein was detected in all mesothelioma cell lines, as well as in the MCF-7 breast cancer cells.
  • Prostaglandin-E2 increased aromatase activity in all five mesothelioma cell lines.
  • Epidermal growth factor significantly increased aromatase activity in MPP89, Ist-Mes2 and Ist-Mes1. The article states it had no effect in NCI-H2452 and MSTO-211H.
  • After 3 hours of treatment with a cytokine mixture, aromatase activity rose significantly in Ist-Mes1 and MPP89.
  • Exemestane significantly reduced growth of the mesothelioma cells. Growth was tested in MPP89, Ist-Mes1 and Ist-Mes2.
  • In the three treated cell lines, exemestane caused cells to accumulate in the S-G2/M phases of the cell cycle, with fewer in G0/G1. A fraction of cells appeared in the sub-G1 compartment, which the authors took to suggest cell death.
  • Exemestane-treated mesothelioma cells showed activation of caspase-3 and PARP, which the authors interpreted as apoptosis (programmed cell death).
  • Exemestane significantly decreased Bcl-xL. It strongly inhibited phosphorylated Akt in Ist-Mes1 and MPP89. Ist-Mes2 had no detectable phosphorylated Akt before treatment.
  • In the 29 tumor specimens, aromatase staining was either negative or located in the cell cytoplasm.
  • In a univariate analysis of the 29 patients, median survival was longer in patients with low to absent aromatase expression than in those with high expression. The p value is printed as 0.001; the symbol before the number did not survive in the text.
  • Tumor histologic type (epithelioid, sarcomatoid, biphasic) did not influence overall survival in this patient group.
• The authors' conclusion: The authors concluded that aromatase is present in malignant mesothelioma and that exemestane can reduce the growth of mesothelioma cells. They suggested that exemestane could open new treatment strategies to be combined with standard therapy, because the Akt pathway and Bcl-xL are implicated in resistance to chemotherapy.
• Limitations the authors state:
  • The patient data were retrospective and observational, so they cannot explain how aromatase might promote tumor growth.
  • The aromatase analysis was done on a small number of patients who were treated in different ways. The authors called for larger independent studies.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Immunohistochemistry, Cytokine, Overall Survival, Chemotherapy.

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