Vitamin D Analogue: Potent Antiproliferative Effects on Cancer Cell Lines and Lack of Hypercalcemic Activity

Ferronato, María Julia; Salomón, Débora Gisele; Fermento, María Eugenia; Gandini, Norberto Ariel; Romero, Alejandro; Rivadulla, Marcos L.; Pérez-García, Xenxo; Gómez, Generosa; Pérez, Manuel; Fall, Yagamare; Facchinetti, María Marta; Curino, Alejandro Carlos

doi:10.1002/ardp.201400448

Cited by 12 publications

(17 citation statements)

References 36 publications

(36 reference statements)

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“…We have previously reported the synthesis of a novel Gemini vitamin D analog, named UVB1, which has two side chains in C-20 and demonstrates potent antitumour effects over a wide panel of tumour cell lines and lacks hypercalcemic activity in mice [16]. In the present study, we have investigated, by employing in vitro and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression.…”

Section: Introductionmentioning

confidence: 96%

The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression

Ferronato

Alonso

Gandini

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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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.

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Section: Introductionmentioning

confidence: 96%

The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression

Ferronato

Alonso

Gandini

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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“…Vitamin D3 (D3), obtained from photoconversion of 7-dehydrocholesterol (7DHC) in the skin or dietary sources, plays an important role in the regulation of many physiological processes such as mineralization, 1 inflammation, 2 and cell proliferation and differentiation. 3 After entering the bloodstream, D3 is carried by D3 binding protein (DBP) and is transported to the liver where it undergoes initial hydroxylation at C25 by the microsomal cytochrome P450 (CYP) enzyme 2R1 (CYP2R1) 4 or mitochondrial CYP27A1 5 to produce 25-hydroxyvitamin D3 [25(OH)D3] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Chemical Synthesis and Biological Activities of 20S,24S/R-Dihydroxyvitamin D3 Epimers and Their 1α-Hydroxyl Derivatives

Lin

Marepally

et al. 2015

J. Med. Chem.

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Bioactive vitamin D3 metabolites 20S,24S-dihydroxyvitamin D3 [20S,24S(OH)2D3] and 20S,24R-dihydroxyvitamin D3 [20S,24R(OH)2D3] were chemically synthesized and confirmed to be identical to their enzymatically generated counterparts. The absolute configurations at C24 and its influence on the kinetics of 1α-hydroxylation by CYP27B1 were determined. Their corresponding 1α-hydroxyl derivatives were subsequently produced. Biological comparisons of these products showed different properties with respect to vitamin D3 receptor activation, anti-inflammatory activity, and antiproliferative activity, with 1α,20S,24R(OH)2D3 being the most potent compound.

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“…Instead, calcitriol produced an increase in total and ionized calcium and decreased the body weight, provoking the death of the animals following 72 h, as previously described [9,11].…”

Section: Ml-344 Decreases the Invasive Capacity Of Mammary Cell Linesmentioning

confidence: 51%

“…Cell migration was evaluated by "wound healing" assays, as previously described [9]. In brief, a confluent monolayer of cells was scratched with a pipette…”

Section: Cell Migration Assaymentioning

confidence: 99%

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

Ferronato

Obiol

Alonso

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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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.

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Vitamin D Analogue: Potent Antiproliferative Effects on Cancer Cell Lines and Lack of Hypercalcemic Activity

Cited by 12 publications

References 36 publications

The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression

The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression

Chemical Synthesis and Biological Activities of 20S,24S/R-Dihydroxyvitamin D3 Epimers and Their 1α-Hydroxyl Derivatives

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

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