seocalcitol and Colonic-Neoplasms

Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Calcitriol; Calcium, Dietary; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Hypercalcemia; Male; Middle Aged

The Wnt/beta-catenin signalling pathway is activated in 90% of human colon cancers by nuclear accumulation of beta-catenin protein due to its own mutation or to that of adenomatous polyposis coli. In the nucleus, beta-catenin regulates gene expression promoting cell proliferation, migration and invasiveness. 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits beta-catenin signalling by inducing its binding to vitamin D receptor (VDR) and by promoting beta-catenin nuclear export. The transcription factor Snail1 represses VDR expression and we demonstrate here that Snail1 also abolishes the nuclear export of beta-catenin induced by 1,25(OH)(2)D(3) in SW480-ADH cells. Accordingly, Snail1 relieves the inhibition exerted by 1,25(OH)(2)D(3) on genes whose expression is driven by beta-catenin, such as c-MYC, ectodermal-neural cortex-1 (ENC-1) or ephrin receptor B2 (EPHB2). In addition, Snail1 abrogates the inhibitory effect of 1,25(OH)(2)D(3) on cell proliferation and migration. In xenografted mice, Snail1 impedes the nuclear export of beta-catenin and the inhibition of ENC-1 expression induced by EB1089, a 1,25(OH)(2)D(3) analogue. The elevation of endogenous SNAIL1 protein levels reproduces the effect of an ectopic Snail1 gene. Remarkably, the expression of exogenous VDR in cells with high levels of Snail1 normalizes the transcriptional responses to 1,25(OH)(2)D(3). However, this exogenous VDR failed to fully restore the blockage of the Wnt/beta-catenin pathway by 1,25(OH)(2)D(3). This suggests that the effects of Snail1 on this pathway are not merely due to the repression of VDR gene. We conclude that Snail1 is a positive regulator of the Wnt/beta-catenin signalling pathway in part through the abrogation of the inhibitory action of 1,25(OH)(2)D(3).

Topics: Animals; beta Catenin; Calcitriol; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colonic Neoplasms; Female; Humans; Mice; Mice, SCID; Microfilament Proteins; Neoplasm Transplantation; Neuropeptides; Nuclear Proteins; Receptors, Calcitriol; Signal Transduction; Snail Family Transcription Factors; Transcription Factors; Vitamin D; Wnt Proteins

Several non-hypercalcemic analogs of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) show antitumor activity in a subset of cancer patients. High vitamin D receptor (VDR) expression, which is associated with good prognosis but is lost during tumor progression. We show that the SNAIL transcription factor represses VDR gene expression in human colon cancer cells and blocks the antitumor action of EB1089, a 1,25(OH)(2)D(3) analog, in xenografted mice. In human colon cancers, elevated SNAIL expression correlates with downregulation of VDR.

Topics: Animals; Antineoplastic Agents; Cadherins; Calcitriol; Colonic Neoplasms; DNA-Binding Proteins; Dose-Response Relationship, Drug; Electrophoretic Mobility Shift Assay; Gene Expression Regulation, Neoplastic; Humans; Immunoprecipitation; Mice; Promoter Regions, Genetic; Receptors, Calcitriol; Snail Family Transcription Factors; Transcription Factors

The beta-catenin signaling pathway is deregulated in nearly all colon cancers. Nonhypercalcemic vitamin D3 (1alpha,25-dehydroxyvitamin D(3)) analogues are candidate drugs to treat this neoplasia. We show that these compounds promote the differentiation of human colon carcinoma SW480 cells expressing vitamin D receptors (VDRs) (SW480-ADH) but not that of a malignant subline (SW480-R) or metastasic derivative (SW620) cells lacking VDR. 1alpha,25(OH)2D(3) induced the expression of E-cadherin and other adhesion proteins (occludin, Zonula occludens [ZO]-1, ZO-2, vinculin) and promoted the translocation of beta-catenin, plakoglobin, and ZO-1 from the nucleus to the plasma membrane. Ligand-activated VDR competed with T cell transcription factor (TCF)-4 for beta-catenin binding. Accordingly, 1alpha,25(OH)2D(3) repressed beta-catenin-TCF-4 transcriptional activity. Moreover, VDR activity was enhanced by ectopic beta-catenin and reduced by TCF-4. Also, 1alpha,25(OH)2D(3) inhibited expression of beta-catenin-TCF-4-responsive genes, c-myc, peroxisome proliferator-activated receptor delta, Tcf-1, and CD44, whereas it induced expression of ZO-1. Our results show that 1alpha,25(OH)2D(3) induces E-cadherin and modulates beta-catenin-TCF-4 target genes in a manner opposite to that of beta-catenin, promoting the differentiation of colon carcinoma cells.

Topics: Active Transport, Cell Nucleus; Adenocarcinoma; Antineoplastic Agents; beta Catenin; Cadherins; Calcitriol; Cell Adhesion Molecules; Cell Differentiation; Cell Membrane; Cholecalciferol; Colonic Neoplasms; Cytoskeletal Proteins; Gene Expression Regulation, Neoplastic; Humans; Ligands; Macromolecular Substances; Phenotype; Protein Binding; Receptors, Calcitriol; RNA, Messenger; Signal Transduction; TCF Transcription Factors; Trans-Activators; Transcription Factor 7-Like 2 Protein; Transcription Factors; Transfection; Tumor Cells, Cultured; Vitamin D