Antitumoral effects of the alkynylphosphonate analogue of calcitriol EM1 on glioblastoma multiforme cells

FERRONATO M.J.; ALONSO E.N.; SALOMÓN D.G.; FERMENTO M.E.; GANDINI N.A.; MASCARÓ E.; VITALE C.; FALL Y.; FACCHINETTI M.M.; CURINO A. C.

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2018 vol. 178 p. 22 - 35

0960-0760

Glioblastoma multiform (GBM) is the worst andmost common brain tumor, characterized by high proliferation and invasionrates. The current standard treatment is mainly based on chemoradiotherapy andthis approach has slightly improved patient survival. Thus, novel strategies aimedat prolonging the survival and ensuring a better quality of life are necessary.In the present work, we investigated the antitumoral effect of the novelanalogue of calcitriol EM1 on GBM cells employing in vitro, in silico, and invivo assays. In vitro, we demonstrated that EM1 treatment selectively decreasesthe viability of murine and human tumor cells without affecting that of normal humanastrocytes. The analysis of the mechanisms showed that EM1 produces cell cyclearrest in the T98G cell line, which is accompanied by an increase in p21, p27,p57 protein levels and a decrease in cyclin D1, p-AktS473,p-ERK1/2 and c-Junexpression. Moreover, EM1 treatment also exerts in GBM cells anti-migratoryeffects and decreases their invasive capacity by a reduction in MMP-9proteolytic activity. In silico, we demonstrated that EM1 is able to bind tothe vitamin D receptor with greater affinity than calcitriol. Finally, weshowed that EM1 treatment of nude mice administered at 50 ug/kg body weightduring 21 days neither induces hypercalcemia nor toxicity effects. Inconclusion, all the results indicate the potential of EM1 analogue as apromising therapeutic alternative for GBM treatment.