The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression

Abstract

Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear β-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.

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

“…6 A and B). As expected in light of our previous results [34] hydrogen bond interactions between calcitriol and Tyr143, Ser237,…”

“…presents the corresponding energies for each interaction component for calcitriol and ML-344 at both pH values.From the analysis of calcitriol component, no significant differences were observed regarding the affinity for VDR at both pH values. In agreement with our previous reports[30,34], the binding of calcitriol at both pHs is mainly stabilizedby Van der Waals interactions (-60.1 and -63.5 Kcal/mol at pH 5.5 and 7, respectively), with a lesser contribution of the EEL component (-33.2 and -27.2…”

Novel Derivatives of Deoxycholic Acid Bearing Linear Aliphatic Diamine and Aminoalcohol Moieties and their Cyclic Analogs at the C3 Position: Synthesis and Evaluation of Their In Vitro Antitumor Potential

“…Particularly, a range of VDR ligands displays a pro-apoptogenic activity—an active metabolite of vitamin D, 1α,25(OH) 2 D 3 , was found to increase Bax/Bcl-2 ratio in leukemia cells [45] and trigger cytochrome c release from mitochondria with subsequent activation of caspase cascade in prostate cancer cells [46]. Apoptosis-inducing activity of VDR ligands was also shown for the Gemini vitamin D analogue of 1α,25(OH) 2 D 3 [47] and diarylmethane skeleton-containing VDR agonist [48] in colon and breast cancer cells, respectively. Beside this, activation of VDR can stimulate autophagy—previously, it was found that 1α,25(OH) 2 D 3 and calcipotriol induce autophagy in breast and colorectal cancer [44,49] and cervical carcinoma [50] cells, respectively.…”

Vitamin D analogues exhibit antineoplastic activity in breast cancer patient-derived xenograft cells

“…We had previously demonstrated that the analogues UVB1 and EM1 decreased cell viability of cell lines coming from different tumor types (colon cancer, head and neck squamous cell carcinoma, glioblastoma multiforme) [12,13,15,16]. Additionally, EM1 displayed anti-metastatic effect [14] in an animal model developed from hormone-independent HER2-positive LM3 cell line, which is derived from a murine mammary adenocarcinoma [19].…”

“…Our group has synthetized two novel non-hypercalcemic vitamin D analogues, UVB1 and EM1, that have demonstrated promising antitumor effects in preclinical studies employing cell lines cultured under 2-dimensional (2D) conditions and in vivo models generated from these cells [12,13,14,15,16].…”