ArticleCancer chemotherapy and pharmacology2014
Anticancer activity of VDR-coregulator inhibitor PS121912.
Article in Cancer chemotherapy and pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- VDR Activation Suppresses Pancreatic Cancer Metastasis Through Inhibition of the ERK Signaling Pathway.Cancers · 2026Article
- Reticuline and Coclaurine Exhibit Vitamin D Receptor-Dependent Anticancer and Pro-Apoptotic Activities in the Colorectal Cancer Cell Line HCT116.Current issues in molecular biology · 2025Article
- Key genes of vitamin D metabolism and their roles in the risk and prognosis of cancer.Frontiers in genetics · 2025Review
- Drug repositioning in thyroid cancer: from point mutations to gene fusions.Frontiers in oncology · 2024Review
- Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer-Implications for Pathogenesis and Therapy.International journal of molecular sciences · 2020Review
- Alternative binding sites at the vitamin D receptor and their ligands.Molecular and cellular endocrinology · 2019Review
- Effects of 1,25 and 24,25 Vitamin D on Corneal Epithelial Proliferation, Migration and Vitamin D Metabolizing and Catabolizing Enzymes.Scientific reports · 2017Article
- Inhibitors for the Vitamin D Receptor-Coregulator Interaction.Vitamins and hormones · 2016Review
- Antitumor Activity of 3-Indolylmethanamines 31B and PS121912.Anticancer research · 2015Article
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15 authors.
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Abstract
purposePS121912 has been developed as selective vitamin D receptor (VDR)-coregulator inhibitor starting from a high throughput screening campaign to identify new agents that modulate VDR without causing hypercalcemia. Initial antiproliferative effects of PS121912 were observed that are characterized herein to enable future in vivo investigation with this molecule.
methodsAntiproliferation and apoptosis were determined using four different cancer cell lines (DU145, Caco2, HL-60 and SKOV3) in the presence of PS121912, 1,25-(OH)₂D₃, or a combination of 1,25-(OH)₂D₃ and PS121912. VDR si-RNA was used to identify the role of VDR during this process. The application of ChIP enabled us to determine the involvement of coregulator recruitment during transcription, which was investigated by RT-PCR with VDR target genes and those affiliated with cell cycle progression. Translational changes of apoptotic proteins were determined with an antibody array. The preclinical characterization of PS121912 includes the determination of metabolic stability and CYP3A4 inhibition.
resultsPS121912 induced apoptosis in all four cancer cells, with HL-60 cells being the most sensitive. At sub-micromolar concentrations, PS121912 amplified the growth inhibition of cancer cells caused by 1,25-(OH)₂D₃ without being antiproliferative by itself. A knockout study with VDR si-RNA confirmed the mediating role of VDR. VDR target genes induced by 1,25-(OH)₂D₃ were down-regulated with the co-treatment of PS121912. This process was highly dependent on the recruitment of coregulators that in case of CYP24A1 was SRC2. The combination of PS121912 and 1,25-(OH)₂D₃ reduced the presence of SRC2 and enriched the occupancy of corepressor NCoR at the promoter site. E2F transcription factors 1 and 4 were down-regulated in the presence of PS121912 and 1,25-(OH)₂D₃ that in turn reduced the transcription levels of cyclin A and D, thus arresting HL-60 cells in the S or G2/M phase. In addition, proteins with hematopoietic functions such as cyclin-dependent kinase 6, histone deacetylase 9 and transforming growth factor beta 2 and 3 were down-regulated as well. Elevated levels of P21 and GADD45, in concert with cyclin D1, also mediated the antiproliferative response of HL-60 in the presence of 1,25-(OH)₂D₃ and PS121912. Studies at higher concentration of P121912 identified a VDR-independent pathway of antiproliferation that included the enzymatic and transcriptional activation of caspase 3/7.
conclusionOverall, we conclude that PS121912 behaves like a VDR antagonist at low concentrations but interacts with more targets at higher concentrations leading to apoptosis mediated by caspase 3/7 activation. In addition, PS121912 showed an acceptable metabolic stability to enable in vivo cancer studies.
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