Vitamin D analogues in colon cancer prevention and care

Abstract

Evidence for a cancer preventive role for vitamin D has been accumulating since the early 1980s, most signifi cantly in blood, breast, and, most notably, colon cancers. Although vitamin D and its metabolites modulate proliferation, angiogenesis, differentiation, and apoptosis, their major function is to maintain calcium homeostasis. Thus, treatment with vitamin D may cause an imbalance of calcium, manifesting in clinical disorders such as hypercalcemia and hypercalciuria. To circumvent these side effects, two branches of research have evolved. The fi rst aims to understand the molecular targets that contribute to the anticancer properties of vitamin D; the second aims to develop vitamin D analogues that retain anticancer properties but have diminished hypercalcemic properties. The purpose of this article is to review the literature regarding failures and successes of vitamin D analogues in colon cancer research.

Vitamin D and Cancer

“…A reduced expression of the enzyme 25 (OH) D-1α-hydroxylase in malignant cells has also suggested but it has not been uniformly observed in all tumor types; Friedrich et al ( 2006 ) described a major expression of the enzyme 25 (OH) D-1α-hydroxylase in breast cancer cells than in healthy breast cells. Moreover, some tumor cell lines, such as breast and colorectal cancer cells, showed an amplification of the expression of the catabolic enzyme 24-hydroxylase (Townsend et al, 2005 ; Beildeck and Byers, 2009 ). All these findings reinforce the concept that higher vitamin D levels represent a protective factor against the onset and progression of cancer.…”

Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment

“…Incidence of colorectal disease is associated with a high fat diet or obesity and with low vitamin D intake. VDR expression actually increases with tumor grade (until very late stage), and poor prognosis is associated with increased levels of vitamin D metabolizing enzymes ([2][7]). An anti-proliferative effect of vitamin D occurs in a wide variety of cancer cell lines and a large number of target genes have been identified that potentially contribute to the anti-proliferative VDR-driven transcriptome.…”

“…As elevated β-catenin is a common occurrence in colon cancer, this strategy would lead to selective activation of anti-proliferative genes in β-catenin-expressing cancer cells. Such a strategy would offer the additional benefit of repressing β-catenin signaling through TCF sites at the same time as VDR is activated ([7]).…”

“…Consequently, one must be cautious when investigating ligand “independent” functions of the VDR as for the most part these are only known to be 1, 25 dihydroxy vitamin D independent and it is possible that they are still able to bind and be activated by other non-canonical ligands, perhaps in a co-activator selective manner. A large number of vitamin D analogs have been identified and screened for their ability to selectively activate the anti-cancer properties of VDR via β-catenin co-activation without promoting calcemic side-effects ([7]). Certain of these VDR analogs (partial antagonists) do not allow recruitment of classical co-activators and therefore cannot activate VDR in most cells.…”

“…These side effects are caused by the rapid response uptake of calcium by the intestine and limit the therapeutic window for vitamin D or its analogs ([7]). In searching for new vitamin D analogs that are preferentially activated at the genomic level in the presence of elevated β-catenin, the ability of such ligands to interact with the non-genomic pool of VDR and influence the calcemic response must also be considered.…”