calcipotriene and Colorectal-Neoplasms

Colorectal cancer (CRC) is an emerging global problem with the rapid increase in its incidence being associated with an unhealthy lifestyle. Epidemiological studies have shown that decreased levels of vitamin D3 significantly increases the risk of CRC. Furthermore, negative effects of vitamin D3 deficiency can be compensated by appropriate supplementation. Vitamin D3 was shown to inhibit growth and induce differentiation of cancer cells, however, excessive vitamin D3 intake leads to hypercalcemia. Thus, development of efficient vitamin D3 analogues with limited impact on calcium homeostasis is an important scientific and clinically relevant task. The aims of the present study were to compare the antiproliferative potential of classic vitamin D3 metabolites (1α,25(OH)2D3 and 25(OH)D3) with selected low calcemic analogues (calcipotriol and 20(OH)D3) on CRC cell lines and to investigate the expression of vitamin D-related genes in CRC cell lines and clinical samples. Vitamin D3 analogues exerted anti-proliferative effects on all CRC cell lines tested. Calcipotriol proved to be as potent as 1α,25(OH)2D3 and had more efficacy than 20-hydroxyvitamin D3. In addition, the analogs tested effectively inhibited the formation of colonies in Matrigel. The expression of genes involved in 1α,25(OH)2D3 signaling and metabolism varied in cell lines analysed, which explains in part their different sensitivities to the various analogues. In CRC biopsies, there was decreased VDR expression in tumor samples in comparison to the surgical margin and healthy colon samples (p<0.01). The present study indicates that vitamin D3 analogues which have low calcemic activity, such as calcipotriol or 20(OH)D3, are very promising candidates for CRC therapy. Moreover, expression profiling of vitamin D-related genes is likely to be a powerful tool in the planning of anticancer therapy. Decreased levels of VDR and increased CYP24A1 expression in clinical samples underline the importance of deregulation of vitamin D pathways in the development of CRC.

Topics: Antineoplastic Agents; Calcifediol; Calcitriol; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Male; Middle Aged; Receptors, Calcitriol; Signal Transduction; Vitamin D; Vitamin D3 24-Hydroxylase

Vitamin D3 reduces human rectal crypt cell production rate (CCPR) and may thereby protect against colorectal cancer. Cell turnover is increased in ulcerative proctocolitis, which might therefore respond to vitamin D3 metabolites. This study investigated the effect of calcipotriol, a synthetic vitamin D3 analogue that avoids hypercalcaemia, on human rectal CCPR in ulcerative proctocolitis. Paired rectal biopsy specimens from seven patients with severe disease were established in organ culture with or without calcipotriol (1 x 10(-6) M). After 15 hours, vincristine (0.6 microgram/ml) was added to induce metaphase arrest, and CCPR was determined by linear regression analysis of accumulated metaphases. Compared with values in 17 controls with incidental anal conditions, median rectal CCPR was 28% higher in ulcerative proctocolitis: 5.90 (5.00-9.50) v 4.80 (2.85-7.07) cells/crypt/hour (p < 0.01). Calcipotriol reduced CCPR by 62% in patients with ulcerative proctocolitis, from 5.90 (5.00-9.50) to 2.21 (0.81-3.22) cells/crypt/hour (median with range) p < 0.01. Thus calcipotriol can dampen the hyperproliferative state in ulcerative proctocolitis and could have a therapeutic role in the control of this inflammatory condition.

Topics: Adult; Aged; Aged, 80 and over; Calcitriol; Cell Division; Colitis, Ulcerative; Colorectal Neoplasms; Depression, Chemical; Epithelium; Female; Humans; Male; Middle Aged; Organ Culture Techniques