IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
LXR/ER modulator as a polypharmacological agent against Breast Cancer
Autor/es:
PALAVICINO, M; BURTON G.; MEDRANO, P; DANSEY MV; AMADO, L; PECCI A
Reunión:
Simposio; SISTAM; 2018
Resumen:
Breast Cancer (BC) is a complex disorder due to multiple genes deregulation, which prompts a robust phenotype. The pharmacological paradigm of ?magic bullets?, targeting individual chemoreceptors, fails as redundant functions are activated and alternative compensatory signaling routes sustain the tumor phenotype, leading to immune escape, chemoresistance and metastasis. In this way, polypharmacology arises as a new paradigm: designing multifunctional selectively non-selective drugs that interact with several molecular targets. This approach would tackle several signaling and metabolic routes at the same time, with one drug, leading to new and more effective treatment against BC. Our hypothesis is that a dual antagonist of both, Estrogen Receptor (ER) and Liver X Receptor (LXR), would inhibit the ER canonical survival routes, but also would inhibit lipogenesis and Warburg effect through LXR antagonism. These two are key metabolic pathways that drive cancer progression, growth, survival, immune evasion, resistance to treatment and disease recurrence.In this sense, we performed a screening of different natural and synthetic oxysterols where Compound 1 emerged as a promising compound. Our unpublished findings proved it is a dual ERα/ERβ antagonist at micro molar concentration, and a dual LXRα/LXRβ inverse agonist at micro molar concentration, in reporter gene assays. 1 effectively inhibits proliferation and migration on the ER+ BC cell line MCF7 and the ER- BC cell line MDA-mb-231. Moreover, it inhibits migration of the human vascular endothelial cell line EA.hy926, by suppressing the NFκB signaling pathway, suggesting antiangiogenic activity. Furthermore, 1 is a natural product, easily obtained in high yields and high degree of purity from a wild plant. The fact that this plant is edible suggests a low toxicity. We present our preliminary studies on 1, with the final intention of validating the dual ER/LXR modulation as a target for polypharmacological agents anti-BC.