Differential antitumoral effects between the analogues of calcitriol SG1 and EM1

Abstract

1α,25-dihydroxyvitamin D3 (calcitriol) shows potent growth-inhibi- tory properties on different cancer cell lines although its hypercal- cemic effects have severely hampered its therapeutic application. Therefore, it is important to develop synthetic analogues that retain or even increase the antitumoral effects without causing hypercalce- mia. Based on the previous evidence of the potent antitumor of the synthetic alkynylphosphonate analogue EM1, we have now synthesized a novel analogue called SG1, which bears a vinylphos- phonate in its side chain. The aim of the present work was to eva- luate the calcemic activity in mice and the antitumor effect of SG1 on different cancer cell lines, comparing them with that exerted by calcitriol and by EM1. In addition, we performed computational mo- deling studies in order to analyze and compare the affinity of the compounds to the vitamin D receptor (VDR). By manual cell count we observed that SG1 exerted a slight decrease in the viability of the HCT116 (IC50: 3,13 nM; p< 0.05) and LM3 (IC50: 0,19 nM; p< 0.001) cell lines whereas it did not affect the viability of HN12, T47D, U251 and T98G cells. By wound healing assays, we observed reductions in the migration rates of the LM3 (p< 0.001) and T98G (p< 0.05) cell lines, whereas it did not affect the migration of the HCT116, U251, GL26, HN12, T47D. Calcemic assays performed in CF1 mice showed that, similarly to EM1, the new analogue SG1 did not cause hypercalcemia (at 5 μg/kg) or toxic effects. Computational studies were performed using as reference the crystallographic structure of the calcitriol-VDR complex (PDB code: 1DB1) and conclude that SG1 binds with lower affinity to VDR than the other two compounds. In conclusion, these results suggest that the modifications in the lateral side chain of analogue SG1 (vinylphosphonate instead of alkynylphosphonate) affect VDR binding affinity and the antitumoral effects previously observed for EM1, while not changing the calce- mic activity