UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Novel LXR/ER modulator as a polypharmacological agent against Breast Cancer
Autor/es:
AMADO, L. D. ; PECCI, A.; MEDRANO, P.; DANSEY, M. V.; PALAVECINO RUIZ, M. D. ; BURTON, G.
Lugar:
Bariloche
Reunión:
Simposio; 4th South American Symposium in Signal Transduction and Molecular Medicine; 2018
Institución organizadora:
SISTAM
Resumen:
Breast Cancer (BC) is a complex disorder due to multiple genes deregulation, whichprompts a robust phenotype. The pharmacological paradigm of ?magic bullets?,targeting individual chemoreceptors, fails as redundant functions are activated andalternative compensatory signaling routes sustain the tumor phenotype, leading toimmune escape, chemoresistance and metastasis. In this way, polypharmacologyarises as a new paradigm: designing multifunctional non-selective drugs that interactwith several molecular targets. This approach would tackle several signaling andmetabolic routes at the same time, with one drug, leading to new and more effectivetreatment against BC. Our hypothesis is that a dual antagonist of both, EstrogenReceptor (ER) and Liver X Receptor (LXR), would inhibit the ER canonical survivalroutes, but also would inhibit lipogenesis and Warburg effect through LXRantagonism. 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 oxysterolswhere Compound 1 emerged as a promising compound. Our unpublished findingsproved it is a dual ERá/ERâ antagonist at micro molar concentration, and a dualLXRá/LXRâ inverse agonist at micro molar concentration, in reporter gene assays. 1effectively inhibits proliferation and migration on the ER+ BC cell line MCF7 and theER- BC cell line MDA-mb-231. Moreover, it inhibits migration of the human vascularendothelial cell line EA.hy926, by suppressing the NFêB signaling pathway, suggestingantiangiogenic activity. Furthermore, 1 is a natural product, easily obtained in highyields and high degree of purity from a wild plant. The fact that this plant is ediblesuggests a low toxicity.We present our preliminary studies on 1, with the final intention of validating thedual ER/LXR modulation as a target for polypharmacological agents anti-BC.