Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas

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 [18F]-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.

Anastrozole Reduce Cell Proliferation and Induce Apoptosis in Glioblastoma Multiforme Xenograft Mouse Model

“…However, Dave et al described that letrozole an AI significantly reduced tumor volume (75%) in a GBM rat model, eight days after the treatment onset. These authors report a marked reduction in aromatase expression [25]. In this work, we also observe a significant reduction in aromatase expression in tumor tissue treated with anastrozole.…”

A review of the carcinogenic potential of bisphenol A

“…Due to the estrogenic action of BPA, this review primarily focuses on in vivo assessments of carcinogenesis in the male and female reproductive tracts as well as other proposed estrogen target tissues (a summary of studies is presented in Table 1). However, we do not exclude any non-reproductive tissues from this analysis as the list of estrogen target tissues continues to expand [33-35]. Similar to the NTP and the International Agency on Research on Cancer (IARC), we evaluate the strength of the evidence to gauge the carcinogenicity of BPA and not the potency of its carcinogenic activity.…”

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

“…Our findings are not only concordant with those reported in conventional glioma cell lines by Dave et al . [41] but also extend these previous findings to a more clinically relevant experimental models such as glioma stem cells by integrating cell type-specific targeting approach based on the utilization of surface biomarkers expressed in GBM cells.…”

“…[41] investigated the efficacy of the aromatase inhibitor, Letrozole, on GBM cell growth in vitro and in vivo exclusively in the conventional human glioma cell lines and the rat glioma C6 cells. Several studies have shown that treatment response in established glioma cells differs greatly to that noted in patient-derived primary cultures [42, 43].…”