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

Abstract

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.

Immunohistochemical expression of vitamin D receptor in melanocytic naevi and cutaneous melanoma: a case-control study

“…As in other neoplasms, tissue VDR status may suggest which patients with MM might be candidates for VD supplementation as an adjuvant treatment. In vitro studies in breast cancer, colon cancer and lung cancer have shown that those cell lines that express VDR respond to VD supplementation with an anticarcinogenic effect …”

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

“…Most recently it was shown that both 20(OH)D3 and 20,23(OH) 2 D3 enhance defense mechanisms against UVB-induced oxidative stress and DNA damage in cultured human keratinocytes [23] and murine skin in vivo [22]. 20(OH)D3 and its hydroxymetabolites also show anti-cancer properties that are cell-lineage dependent [53, 54, 64, 68, 69, 88, 90, 92–97]. …”

Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

“…The hydroxyvitamin D 3 metabolites produced by these pathways, including the major product, 20(OH)D 3 , are biologically active in both in vitro (reviewed in [8]) and in vivo [22] models. Since they are less prone to induce hypercalcemia than 1,25(OH) 2 D 3 [23, 24], they deserve special attention as potential therapeutics for the treatment of leukemia [23], melanoma [10, 11, 25, 26] and colorectal cancer [27]. …”