Differential antitumor effects of vitamin D analogues on colorectal carcinoma in culture

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 D(3) significantly increases the risk of CRC. Furthermore, negative effects of vitamin D(3) deficiency can be compensated by appropriate supplementation. Vitamin D(3) was shown to inhibit growth and induce differentiation of cancer cells, however, excessive vitamin D(3) intake leads to hypercalcemia. Thus, development of efficient vitamin D(3) 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 D(3) metabolites (1α,25(OH)(2)D(3) and 25(OH)D(3)) with selected low calcemic analogues (calcipotriol and 20(OH)D(3)) on CRC cell lines and to investigate the expression of vitamin D-related genes in CRC cell lines and clinical samples. Vitamin D(3) analogues exerted anti-proliferative effects on all CRC cell lines tested. Calcipotriol proved to be as potent as 1α,25(OH)(2)D(3) and had more efficacy than 20-hydroxyvitamin D(3). In addition, the analogs tested effectively inhibited the formation of colonies in Matrigel. The expression of genes involved in 1α,25(OH)(2)D(3) 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 D(3) analogues which have low calcemic activity, such as calcipotriol or 20(OH)D(3), 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.