ANTITUMORAL EFFECTS OF A NOVEL GEMINI VITAMIN D ANALOGUE

FACCHINETTI. M.M.; ALONSO, E.N.; OBIOL, D. J.; GANDINI, N.A.; FERMENTO, M.E.; FALL, Y.; CURINO, A.C.; FERRONATO, M.J.

San Carlos de Bariloche

Congreso; Sistam 2015; 2015

CONICET

1α,25-dihydroxyvitaminD3 (calcitriol) shows potent growth-inhibitory properties ondifferent cancer cell lines although its hypercalcemic effects have severelyhampered its therapeutic application. Therefore, structural analogues are beingdesigned and synthesized with the aim at finding one that exerts antitumoreffects with lack of calcemic activity. In collaboration with the laboratory ofOrganic Chemistry of the University of Vigo we synthesized a novel Geminianalogue of calcitriol, called UVB1. The aim of this study was to evaluate theantitumor action of UVB1 on different cell lines, comparing its effects withthose elicited by calcitriol, and investigate analogue effects on a colorectalcarcinoma animal model. The results show that the analogue retards cellmigration (p  <0.001) and invasion (p <0.001)of the murine mammary adenocarcinoma LM3 cell line while cell motility andinvasiveness of the normal murine mammary epithelial HC11 cell line are notaffected. The phalloidin staining of the F-actin LM3 filaments shows areduction in the amount of stress fibers compared with the control (p <0.001).The analysis of E-cadherin expression by immunofluorescence and western blot inUVB1-treated LM3 cells shows an increase in E-cadherin protein expression respectto vehicle (p <0.01). The β-catenin expression is not affected. Also, theanalog exerts a significant increase in p27kip1 expression in thesame cell line (p <0.01). UVB1 reduces also cell viability of human colorectalcarcinoma HCT116 cell line (p <0.001) and tumor volume (4.98 ± 1.34 cm3versus 1.81 ± 0.29 cm3, p <0.05) in a xenograft animal model(UVB1 40 µg/kg). Additionally, the treatment of N:NIH(S)-Fox1nu micewith 40 ug/kg of the analogue does not produce hypercalcemia, kidney or liverhistological alterations, changes in behavior, weight loss or haematocritalterations. In conclusion, these results suggest that this Gemini analogue mayhave therapeutic potential as an antitumor drug.