Synthesis of a novel analog of calcitriol and its biological evaluation as antitumor agent

Abstract

Calcitriol analogs have shown promising potential as compounds to be used in cancer chemotherapy. This report presents the synthesis of a novel vitamin D derivative with an amide and a carboxyl group in its side chain, called ML-344. In addition, we report its in vitro antitumor activity and its in vivo calcemic effects. We demonstrate that the analog decreases cell viability and retards cell migration of different breast, glioblastoma and head and neck cancer cell lines. Additionally, unlike calcitriol, ML-344 does not display citotoxicity to the murine non-malignant mammary cells and human astrocytes. In concordance with the antimigratory effects found in breast cancer cells, ML-344 decreased the invasive capacity and induced a rearrangement of the actin cytoskeleton in the LM3 breast cancer cell line. In relation to the in vivo studies, the analog did not cause hypercalcemic effects in CF1 mice administered daily at 5 μg/Kg of body weight during a period of 264 h. Finally, computational studies were performed to evaluate the potential binding of the analog to the vitamin D receptor and the in silico assays showed that ML-344 is able to bind to VDR with interesting particularities and greater affinity than calcitriol. Altogether, these results suggest that ML-344 has a promising potential as an antitumor agent with a differential effect between tumor and non-malignant cells.

Effects of vitamin D in the nervous system: Special focus on interaction with steroid hormone signalling and a possible role in the treatment of brain cancer

“…A number of findings indicate that 1,25‐dihydroxyvitamin D 3 can stimulate differentiation and suppress proliferation in several cell types . In addition to the suppression of proliferation, 1,25‐dihydroxyvitamin D 3 can also affect viability . The effects may vary in different cells and under different conditions.…”

“…Vitamin D analogues have been shown to inhibit both cellular growth and viability in various types of cancer cells . So far, relatively few studies have been conducted on tumours of the nervous system . Most of these studies have been performed on different types of glioma cells.…”

“…There was, however, no induction of apoptosis by either 1,25‐dihydroxyvitamin D 3 or vitamin D analogues in these cells. Ferronato et al investigated the actions of the experimental alkynylphosphonate vitamin D analogue EM1 in glioblastoma T98G and U251 cells. This analogue produced cell cycle arrest in T98G cells without affecting the viability of normal astrocytes.…”

In Vitro and In Vivo Antitumor Activity of Vitamin D3 in Malignant Gliomas: A Systematic Review

“…Ferronato et al (16) examined the effect of a synthetic novel derivative of vitamin D3 called ML-344 on in vitro antitumor activity and in vivo calcemic effects. They also had the computational studies to examine its affinity for VDR through in silico assays.…”

“…Beyond the calcium balance role of vitamin D and the beneficial effects on bone, due to the existence of vitamin D receptor (VDR) throughout body especially in the brain, vitamin D regulates the various types of function such as cell proliferation and differentiation, apoptosis, angiogenesis, cell invasion, DNA repair, metabolism, and inflammation (12)(13)(14). Although antitumor efficacy of vitamin D3 is observed in supraphysiological doses, which in turn may cause hypercalcemia, recent in vivo studies have shown that its analogs have beneficial effects on glioma cells without calcemic effect (15)(16)(17)(18). Here, we review studies about the effect of vitamin D3 and its analogs on gliomas with special emphasis on GBM.…”