The aromatase inhibitor letrozole and inhibitors of insulin-like growth factor I receptor synergistically induce apoptosis in in vitro models of estrogen-dependent breast cancer

INTRODUCTION: Endocrine-dependent, estrogen receptor positive breast cancer cells proliferate in response to estrogens, synthesized by the cytochrome p450 aromatase enzyme. Letrozole is a potent nonsteroidal aromatase inhibitor that is registered for the treatment of postmenopausal women with advanced metastatic breast cancers and in the neoadjuvant, early, and extended adjuvant indications. Because crosstalk exists between estrogen receptor and insulin-like growth factor I receptor (IGF-IR), the effect of combining a selective IGF-IR inhibitor (NVP-AEW541) with letrozole was assessed in two independent in vitro models of estrogen-dependent breast cancer. METHODS: MCF7 and T47D cells stably expressing aromatase (MCF7/Aro and T47D/Aro) were used as in vitro models of aromatase-driven breast cancer. The role of the IGF-IR pathway in breast cancer cells stimulated only by 17ß-estradiol or androstenedione was assessed by proliferation assays. The combination of letrozole and NVP-AEW541 was assessed for synergy in inhibiting cell proliferation using Chou-Talalay derived equations. Finally, combination or single agent effects on proliferation and apoptosis were assessed using proliferation assays, flow cytometry, and immunoblotting. RESULTS: Both MCF7 and T47D cells, as well as MCF7/Aro and T47D/Aro, exhibited sensitivity to inhibition of 17ß-estradiol dependent proliferation by NVP-AEW541. Letrozole combined with NVP-AEW541 synergistically inhibited androstenedione-dependent proliferation in aromatase-expressing cells with combination index values of 0.6 or less. Synergistic combination effects correlated with higher levels of apoptosis as compared with cells treated with the single agent alone. Treatment with either agent also appeared to inhibit IGF-IR signalling via phosphoinositide 3-kinase. Notably, IGF-IR inhibition had limited effect on estrogen-dependent proliferation in the cell lines, but was clearly required for survival, suggesting that the combination of letrozole and IGF-IR inhibition sensitizes cells to apoptosis. CONCLUSION: Inhibition of the IGF-IR pathway and aromatase was synergistic in two independent estrogen-dependent in vitro models of breast cancer. Moreover, synergism of NVP-AEW541 and letrozole correlated with induction of apoptosis, but not cell cycle arrest, in the cell lines tested. Combination of IGF-IR inhibitors and letrozole may hold promise for the treatment of patients with estrogen-dependent breast cancers

Cinco años de la Revista Argentina de Ciencias del Comportamiento. Logros y desafíos

At the end of 2009, the first issue of the Revista Argentina de Ciencias del Comportamiento (RACC) appeared, the result of the joint effort of Marcos Cupani (general editor), Ricardo Pautassi (technical editor) and Juan Carlos Godoy (executive editor), with the endorsement of the Asociación Argentina de Ciencias del Comportamiento (AACC) and the Faculty of Psychology of the National University of Córdoba. As stated in that first issue, the purpose of the RACC was (and is) to promote the national and international dissemination of research in the area of human and animal behavioral sciences, through a freely accessible format.A fines del año 2009 apareció el primer número de la Revista Argentina de Ciencias del Comportamiento (RACC), fruto del esfuerzo conjunto de Marcos Cupani (editor general), Ricardo Pautassi (editor técnico) y Juan Carlos Godoy (editor ejecutivo), con el aval de la Asociación Argentina de Ciencias del Comportamiento (AACC) y la Facultad de Psicología de la Universidad Nacional de Córdoba. Tal como se señalaba en ese primer número, el propósito de la RACC era (y es) promover la difusión nacional  e  internacional  de  las investigaciones en el área de las ciencias que se ocupan del comportamiento humano y animal, a través de un formato de libre acceso

Editorial

We began 2014 with a balance of achievements and a proposal of goals to achieve in the medium and long term. At the end of the year, we are pleased to announce the progress made and to present the articles included in the sixteenth issue of the Revista Argentina de Ciencias del Comportamiento (RACC).Comenzamos el año 2014 con un balance de los logros y una propuesta de metas para alcanzar en el mediano y largo plazo. Ya culminando el año, nos complace comunicar los avances alcanzados y presentar los artículos que comprende el dieciseisavo número de la Revista Argentina de Ciencias del Comportamiento (RACC)

Conveni de col·laboració entre l'ICUB i la Fundació RACC

Aprovat entre l'ICUB i la Fundació RACC el 02-02-202