Antitumoral effects and calcemic activity of the novel analogue of calcitriol ML-344

FERRONATO M.J.; OBIOL D.J.; ALONSO E.N.; GUEVARA J.A.; FERMENTO M.E.; GANDINI N.A.; QUEVEDO M.A.; FALL Y.; LOIS M; GOMEZ G.; CURINO A. C.; FACCHINETTI M.M.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias. LXII Reunión Anual de la Sociedad Argentina de Investigaciones Clínicas (SAIC); 2017

Sociedad Argentina de Investigaciones Clínicas (SAIC)

The active form of vitamin D3, calcitriol, has been shown to display antitumoral effects on various types of cancer. However, hypercalcemia is observed when effective antitumoral doses of calcitriol are employed, thus precluding its therapeutic application. In collaboration with the laboratory of Organic Chemistry of the University of Vigo we synthesized an analogue of calcitriol, called ML-344, in order to obtain a compound that retain or even increase the antitumoral activity but prevent the side effects. In this work we aimed to evaluate the biological effects of ML-344 by employing in vitro, in vivo and in silico assays. We demonstrated that the analogue exerts a significant decrease in the viability of different cancer cell lines (p< 0.001): head and neck squamous cell carcinoma (HN12), glioblastoma multiforme (GL26 and U251) and breast adenocarcinoma (4T1 and LM3) cells. Importantly, the cellular viability of human primary astrocytes and murine non-malignant mammary epithelial HC11 cell line is not affected after ML-344 treatment. Also, the analogue retards cell migration of 4T1 and LM3 cells (16 h: p< 0.001; 21 h: p< 0.01) while it does not affect HC11 cell motility. In concordance with the antimigratory effects, ML-344 decreases LM3 invasive capacity(p< 0.01) and induces a rearrangement of actin cytoskeleton by a reduction in the amount of cells with stress fibers (p< 0.001). In vivo studies showed that the analogue, in contrast to calcitriol, does not cause hypercalcemic effects in CF1 mice administrated daily at 5 µg/Kg of body weight during 96 h. In addition, hematocrit remained within the normal levels and no changes in body weight were found. Finally, computational studies showed that ML-344 is able to bind to VDR with greater affinity than calcitriol (∆G= -82.5 and -73.5 Kcal/mol, respectively). Altogether, these results suggest the potential use of this analogue as an antitumor drug with a differential effect between tumor and non-malignant cells.