Combination therapy of paclitaxel with UVB11: a new therapeutic option for aggressive breast carcinomas

Abstract

Hormone-independent and Triple-Negative (TN) Breast Cancer (BC) are aggressive tumors that are treated with therapies such as anti-HER2 and cytotoxic chemotherapy, respectively. These tumors have bad prognosis and their therapeutic strategies provoke adverse side effects. Therefore, the identification of an alternative approach to treat these BC is needed. Our laboratory studies the antitumor properties of a non-hypercalcemic calcitriol analog called UVB1 that has previously demonstrated antineoplastic effects in different types of cancer. The aim of this work is to evaluate the antitumor effects of UVB1 on aggressive BC cells, either alone or in combination with paclitaxel (PTX). To this end, cell viability was evaluated by crystal violet assays in 4T1 and MDA-MB-231 TNBC cell lines treated with vehicle, UVB1, PTX or combination of drugs. The results show that UVB1 (1000 nM) with low concentrations of PTX display a greater reduction in viability with respect to control and monotherapies in both cell lines (120 and 48 h of treatment, respectively). Combination indexes (CI) obtained by Chou-Talalay method were less than 1, which indicates synergism between UVB1 and PTX. These effects are maintained with a lower UVB1 concentration (1 nM) in both cell lines. Molecular modeling studies, including molecular docking and molecular dynamics simulations, suggest a cooperative binding mode 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 favours the AF-2 conformation that resembles the one observed for the natural substrate calcitriol. Altogether, these results suggest the potential combination of a calcitriol analogue with lower doses of conventional chemotherapeutics for aggressive BC treatment.