Combination therapy of paclitaxel with calcitriol analogues: a new therapeutic option for Triple Negative Breast Cancer

Agustina Ibarra¹, Josefina Guevara¹, Giuliana Paolillo¹, Valentina Clemente¹, Alfredo Quevedo², Yagamare Fall³, Cristian Vitale⁴, Evangelina Mascaró4, María Julia Ferronato¹, María Marta Facchinetti¹, Curino Alejandro Carlos¹

Triple Negative Breast Cancer (TNBC) is a heterogeneous group of tumors with high mortality and poor prognosis. Therefore, new therapeutic strategies are needed. Previously, the non-hypercalcemic calcitriol analogues EM1 and UVB1 have demonstrated promising antitumoral effects in BC cells. Hence, the aim of this work was to evaluate the effects of the analogues combined with paclitaxel (PTX) on the viability and migration of TNBC cells. The results show that EM1 or UVB1 in combination with low concentrations of PTX display a greater reduction of the viability of 4T1- murine TNBC cells, with respect to control and with the monotherapy. The Combination Index (CI) values of Chou & Talalay method were 0.03 and 0.01 for EM1–PTX and UVB1–PTX combinations, respectively, indicating a synergistic effect. Additionally, these viability effects were lost when the Vitamin D Receptor (VDR) was silenced in the cells, suggesting that VDR is necessary for the antitumoral effects. Moreover, the cell cycle analysis of 4T1 cells treated with UVB1-PTX combination showed arrest in GO/G1 at 72 h followed by cell death at 120 h of treatment. Also, we found a synergistic effect by combining EM1 and PTX in MDA-MB-231- human TNBC cells (CI value: 0.0002). Finally, UVB1-PTX combination displayed antimigratory effects on 4T1 cell line. Altogether, these results suggest the potential use of these novel calcitriol analogues in combination with the conventional chemotherapy in TNBC treatment.