title: 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 [(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.
authors.affiliation: The James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Nimita
authors.initials: N
authors.lastname: Dave
authors.affiliation: Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Lionel M L
authors.initials: LM
authors.lastname: Chow
authors.affiliation: The James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gudelsky
authors.affiliation: Vontz Core Imaging Lab, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Kathleen
authors.initials: K
authors.lastname: LaSance
authors.affiliation: Internal Medicine, Department of Hematology/Oncology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Qi
authors.affiliation: The James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio. desaipb@ucmail.uc.edu.
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Desai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D005910:Glioma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D000077289:Letrozole; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051381:Rats; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase; D019363:Cytochrome P-450 CYP1A1