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The secosteroid hormone 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has potent antiproliferative and prodifferentiating actions on a wide variety of normal as well as malignant cell types. Strong calcemic effects obstruct the actual application of 1,25-(OH)2D3 for the treatment of hyperproliferative disorders such as cancer. To overcome this problem, structural analogs of 1,25-(OH)2D3 have been designed with a clear dissociation between antiproliferative and calcemic effects. This review focuses on the molecular mode of action of different 1,25-(OH)2D3 analogs and, in particular, on the recruitment of cofactor molecules to the vitamin D receptor by these analogs.

In search of photoprotective agents, we recently demonstrated a protective effect of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] against different events mediated by ultraviolet B (UVB) in human keratinocytes. Pharmacological doses of 1,25(OH)(2)D(3) were required to obtain significant UVB protection; however, these doses cannot be used in vivo due to the calcemic properties of 1,25(OH)(2)D(3). Therefore, we evaluated the photoprotective capacities of two low-calcemic 14-epi analogues of 1,25(OH)(2)D(3), 19-nor-14-epi-23-yne-1,25(OH)(2)D(3) (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3) (TX 527). Using cultured human keratinocytes, we investigated the influence of TX 522 and TX 527 on two hallmark events in UVB-irradiated keratinocytes: the induction of apoptosis and the production of interleukin-6 (IL-6). Treatment of the keratinocytes with TX 522 or TX 527, 24 h before irradiation, resulted in a significant and dose-dependent reduction of both UVB-induced apoptosis and IL-6 production. Both analogues were equally efficient in their anti-UVB effects and at least 100 times more potent than 1,25(OH)(2)D(3). We further demonstrated that metallothionein (MT) mRNA expression was clearly induced by 1,25(OH)(2)D(3) and both analogues. MT acts as a radical scavenger in oxygen-mediated UVB injury and its induction may therefore be relevant for the anti-UVB effects of 1,25(OH)(2)D(3) and both analogues. Taken together, these findings create new perspectives for the use of active vitamin D analogues as photoprotective agents.

A novel series of analogs of 1,25-dihydroxyvitamin D3, the hormonally active metabolite of vitamin D3, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive. The molecular origin of this behavior is still under study.

The development of less calcemic vitamin D analogs creates possible therapeutic applications for immune modulation (e.g., autoimmune diseases and graft rejection), inhibition of cell proliferation and induction of cell differentiation (e.g., cancer). Recently more insight was obtained in the mechanism of action of the analogs at the biological and molecular level. Critical remarks are summarized on why the step towards the clinic has not yet been taken and how better selective vitamin D receptor modulators could be designed.

Analogs of vitamin D have been synthesized which have reduced calcemic activities yet increased anti-proliferative and differentiation-inducing properties, raising expectations that they will be useful for treatment of human neoplastic diseases. In the present study we compared the abilities of three such analogs, 24a, 24b-dihomo-1,25-dihydroxyvitamin D(3) (PRI-1890), 24-ene-1,25-dihydroxyvitamin D(2) (PRI-1906) and (24R)-1,24-dihydroxyvitamin D(3) (PRI-2191) to induce markers (CD14, CD11b and MSE) of differentiation, G(1) phase block, and associated molecular events in human promyeloblastic leukemia cells HL60. We found that the potencies of the analogs to induce differentiation paralleled their activation of Erk, JNK and p38 mitogen-activated protein kinase (MAPK) pathways, and the anti-proliferative activity closely correlated with the extent of hypophosphorylation of retinoblastoma protein (pRb). Interestingly, low concentrations of derivatives of vitamin D, which were insufficient to induce any detectable changes in the cell cycle traverse, markedly increased the levels of total pRb, which was highly phosphorylated. These results suggest that pRb may have an unsuspected role in monocytic differentiation, perhaps to increase the sensitivity of the G(1) checkpoint, by increasing the amount of substrate for cyclin-dependent kinases.