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Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas
Nimita Dave1, Lionel M L Chow2, Gary A Gudelsky1
1The James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
Abstract:
We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor-positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague-Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing μPET/CT imaging, employing [(18)F]-fluorodeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines included here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1-3.5 μmol/L). Imaging analysis employing F18-FDG μPET/CT demonstrated a marked reduction of active tumor volume (>75%) after 8 days of letrozole treatment. Immunohistochemical analysis revealed marked reduction in aromatase expression in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aromatase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options.
Insights
Letrozole, an aromatase inhibitor, shows promise for treating glioblastomas. This study found letrozole effectively reduced glioma cell activity and tumor volume in preclinical models, suggesting a new therapeutic avenue.
Area of Science:
- Neuro-oncology
- Pharmacology
- Biochemistry
Background:
- Glioblastomas are aggressive primary brain tumors with limited treatment options.
- Aromatase (CYP19A1) is implicated in various cancers, and its role in gliomas is under investigation.
- Letrozole is an established aromatase inhibitor for breast cancer treatment.
Purpose of the Study:
- To investigate the in vitro and in vivo efficacy of letrozole in glioma models.
- To determine if aromatase is a viable therapeutic target for gliomas.
- To explore the potential repurposing of letrozole for glioma treatment.
Main Methods:
- In vitro cytotoxicity assays (MTT) and aromatase activity measurements in human and rat glioma cell lines.
- In vivo assessment of letrozole's effect on tumor volume using F18-FDG μPET/CT imaging in a rat glioma model.
- Histological and immunohistochemical analyses of brain tissues to evaluate aromatase expression.
Main Results:
- All tested glioma cell lines expressed aromatase (CYP19A1).
- Letrozole demonstrated significant in vitro cytotoxicity and reduced aromatase activity in glioma cells (IC50: 0.1-3.5 μmol/L).
- In vivo studies showed a >75% reduction in active tumor volume after 8 days of letrozole treatment, with decreased tumoral aromatase expression.
Conclusions:
- Aromatase is a potential novel therapeutic target for gliomas.
- Letrozole, an FDA-approved drug, shows significant preclinical efficacy against gliomas.
- Repurposing letrozole may offer a new treatment strategy for primary brain tumors with limited options.
