INVESTIGADORES
CURINO Alejandro Carlos
congresos y reuniones científicas
Título:
Synergistic combination of paclitaxel with novel non-hypercalcemic calcitriol analog EM1 against triple negative breast cancer cells: new mechanism of action
Autor/es:
GUEVARA J.A.; IBARRA A.; FERRONATO M.J.; ALONSO E.G.; VITALE C.; MASCARÓ E.; QUEVEDO M.A.; COLO G.P.; FERMENTO M.E.; FACCHINETTI M.M.; CURINO A. C.
Lugar:
Mar del Plata
Reunión:
Congreso; Reunión Anual de Sociedades de Biociencias. LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC).; 2022
Institución organizadora:
Sociedad Argentina de Investigación Clínica (SAIC).
Resumen:
Hormone-independent and Triple-Negative (TN) Breast Cancer(BC) are aggressive tumors that are treated with therapies such asanti-HER2 and cytotoxic chemotherapy, respectively. These tumorshave bad prognosis and their therapeutic strategies provoke adverseside effects. Therefore, the identification of an alternative approachto treat these BC is needed. Our laboratory studies the antitumorproperties of a non-hypercalcemic calcitriol analog called UVB1 thathas previously demonstrated antineoplastic effects in different typesof cancer. The aim of this work is to evaluate the antitumor effectsof UVB1 on aggressive BC cells, either alone or in combination withpaclitaxel (PTX). To this end, cell viability was evaluated by crystalviolet assays in 4T1 and MDA-MB-231 TNBC cell lines treated withvehicle, UVB1, PTX or combination of drugs. The results show thatUVB1 (1000 nM) with low concentrations of PTX display a greaterreduction in viability with respect to control and monotherapies inboth cell lines (120 and 48 h of treatment, respectively). Combination indexes (CI) obtained by Chou-Talalay method were less than1, which indicates synergism between UVB1 and PTX. These effects are maintained with a lower UVB1 concentration (1 nM) in bothcell lines. Molecular modeling studies, including molecular docking and molecular dynamics simulations, suggest a cooperative bindingmode to VDR of UVB1 and PTX, which in turn elicits a close regulation of the conformational behaviour of the activating factor 2 (AF-2)region of VDR. The combination of UVB1 and PTX strongly favoursthe AF-2 conformation that resembles the one observed for the natural substrate calcitriol. Altogether, these results suggest the potentialcombination of a calcitriol analogue with lower doses of conventionalchemotherapeutics for aggressive BC treatment.