Novel calcitriol analogues EM1 and UVB1 against aggressive breast cancer cells as a monotherapy or in combination with paclitaxel

Abstract

Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer (BC), its effectiveness is limited by intrinsic or acquired resistance and associated adverse effects. Therefore, new therapeutic strategies are needed. Previously, we demonstrated that the calcitriol analogue EM1 decreases the viability, migration and invasion of the 4T1 triple-negative BC (TNBC) cells. Additionally, we reported that UVB1, another calcitriol analogue synthetized by our group, reduces the viability of cells derived from the TNBC - Patient-Derived Xenografts (PDX). Hence, the aim of the present study was to continue evaluating the antitumoral effects of the calcitriol analogues EM1 and UVB1 on aggressive BC cells, alone or in combination with low concentrations of Paclitaxel (PTX). We found a synergistic effect by combining EM1 or UVB1 with non- effective PTX concentrations on viability of 4T1 cells. The resulting Combination Index values of Chou & Talalay method were 0.80059 and 0.13491 for EM1-PTX and UVB1-PTX combinations, respectively. In addition of our previous result on 4T1 cell migration, EM1 displayed antimigratory effects on MDA- MB-231 TNBC cell line (p<0.001). In contrast, UVB1 had no effect on these cells. However, interestingly, the combination of the analogues with non-effective concentrations of PTX over 4T1 cell migration displayed a better effect than drugs alone (EM1- PTX: p<0.05; UVB1-PTX: p<0.001). Finally, a pilot in vivo assay was conducted to test the sensitivity of the TNBC-PDX410 to UVB1. A reduction in in vivo tumor volume was detected after 18 days of UVB1 treatment at 40 μg/kg of body weight administrated three times a week (p<0.05). Altogether, these results suggest the potential use of these vitamin D analogues as antitumor agents, alone or as a complement to conventional chemotherapy.