Antitumoral effects of the vitamin D analogue EM1 on glioblastoma multiforme cell lines

FERRONATO, M.J.; OBIOL, D. J.; LÓPEZ ROMERO, A.; FACCHINETTI, M.M.; ALONSO, E.N.; GANDINI, N.A.; MASCARÓ, E.; CURINO, A.C.; FERMENTO, M.E.; QUEVEDO, M.A.; VITALE, C.

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigaciones Clínicas (SAIC); 2016

Sociedad Argentina de Investigación Clínica (SAIC)

Currently, firstline adjuvant treatment for glioblastoma is based on the combination of radiotherapy and temozolomide. Although the combination treatment has slightly improved patient survival, novel strategies aimed at prolonging the survival and ensuring a better quality of life are necessary. E/ is a novel calcitriol analogue Yith antitumoral properties and, as a steroid compound, has the potential to cross the bloodbrain barrier. The aim of the present study Yas to evaluate the potential of E/ as a chemosensitizing agent in glioblastoma treatment by investigating its antitumoral effects on human T) and 7 cells, and modeling E/ binding to its receptor 8&4 by in silico assays. +n culture results shoYed that the analogue exerts a significant decrease in T) cell viability through cell cycle arrest in )/) phase p .. This result Yas accompanied by an increase in the expression of p, p and 8&4 and a decrease in cyclin & and pA-T, assayed by Yestern blot. /oreover, the treatment Yith E/ did not affect cellular viability 9ST of human primary astrocytes, thus demonstrating a differential effect on nonmalignant cells. E/ Yas also able to retard 7 and T) migration p . in Yound healing assays and to inhibit T) cell invasion p . through /atrigel. The binding of E/ to 8&4 Yas explored by means of molecular docMing and molecular dynamics. 2erresidue interaction analyses shoYed that E/ is able to bind to 8&4 establishing intermolecular contacts Yith most of the residues that interact Yith calcitriol. Energetic analysis shoYed a higher affinity of E/ for 8&4 than calcitriol ţ) . and . -cal/mol, respectively. There Yere significant electrostatic interactions betYeen the phosphate group present in this ligand and His of 8&4 and additional 8an der 9aals interactions that further enhanced the affinity of E/ for 8&4. Altogether, these results suggest the potential use of this analogue in glioblastoma treatment.