Differential antitumoral effects between the analogues of calcitriol SG1 and EM1

GRIOLI, S.M.; FERRONATO, M.J.; OBIOL, D.J.; GUEVARA, J.A.; QUEVEDO, M.A.; RADIVOY, C. ; VITALE, C.; CURINO, A.C.; FACCHINETTI, M.M.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

1α,25-dihydroxyvitamin D3 (calcitriol) shows potent growth-inhibitoryproperties on different cancer cell lines although its hypercalcemiceffects have severely hampered its therapeutic application.Therefore, it is important to develop synthetic analogues that retainor even increase the antitumoral effects without causing hypercalcemia.Based on the previous evidence of the potent antitumor effectsof the synthetic alkynylphosphonate analogue EM1, we have nowsynthesized a novel analogue called SG1, which bears a vinylphosphonatein its side chain. The aim of the present work was to evaluatethe calcemic activity in mice and the antitumor effect of SG1on different cancer cell lines, comparing them with that exerted bycalcitriol and by EM1. In addition, we performed computational modelingstudies in order to analyze and compare the affinity of thecompounds to the vitamin D receptor (VDR). By manual cell countwe observed that SG1 exerted a slight decrease in the viability of theHCT116 (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, U251and T98G cells. By wound healing assays, we observed reductionsin 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 miceshowed that, similarly to EM1, the new analogue SG1 did not cause hypercalcemia (at 5 μg/kg) or toxic effects. Computational studieswere performed using as reference the crystallographic structureof the calcitriol-VDR complex (PDB code: 1DB1) and conclude thatSG1 binds with lower affinity to VDR than the other two compounds.In conclusion, these results suggest that the modifications in thelateral side chain of analogue SG1 (vinylphosphonate instead ofalkynylphosphonate) affect VDR binding affinity and the antitumoraleffects previously observed for EM1, while not changing the calcemicactivity.