Novel Vitamin D Analogs for Prostate Cancer Therapy

Abstract

Prostate cells contain specific receptors for 1α,25-dihydroxyvitamin D [1α,25(OH)2D] or calcitriol, the active form of vitamin D. 1α,25(OH)2D is known to inhibit the proliferation and invasiveness of prostate cancer cells. These findings support the use of 1α,25(OH)2D for prostate cancer therapy. However, 1α,25(OH)2D can cause hypercalcemia, analogs of 1α,25(OH)2D that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. To accomplish these goals, different strategies, based on metabolism, molecular mechanism of actions, and structural modeling, have been taken to modify the structure of vitamin D molecule with the aims to improve the efficacy and decrease the toxicity of vitamin D to treat different diseases. During the past four decades, over 3,000 analogs have been synthesized. In this paper, we discuss the development and the biological analysis of a unique class of vitamin D analogs with a substitution at the carbon 2 of 19-nor-1α,25(OH)2D3 molecule for potential application to the prevention and treatment of prostate cancer as well as other cancers.

Vitamin D in cancer chemoprevention

“…These investigations have shown that both analogues possess antiproliferative activity comparable with that of 1,25(OH) 2 D 3 . However, MART-10 proves about 1000-fold more active than 1a,25(OH) 2 D 3 in inhibiting LNCaP and PC-3 prostate cancer cell proliferation (Chen & Kittaka, 2011;Iglesias-Gato et al, 2011). Furthermore, in vitro studies which compared the expression level of the enzyme CYP24A1 in LNCaP and PC-3 in response to treatment with 1,25(OH) 2 D 3 and MART-10 showed that this latter molecule was able to induce the expression of CYP24A1, one of the three major enzymes involved in the metabolism of Vit D (Jones et al, 2012), to a lower concentration than calcitriol (Flanagan et al, 2009).…”

“…However, the hypercalcemic effects induced by 1,25(OH) 2 D 3 have strongly limited its therapeutic use Mehta, 2012). Therefore, many efforts are currently being directed towards synthesizing new Vit D analogues with the goal of improving the biological profile of the natural hormone, which retains the therapeutic activity the analogues being endowed with a lower calcemic effect (Byers et al, 2012;Chen & Kittaka, 2011;Fleet et al, 2012;Trump et al, 2010). Vit D analogues are semi-synthetic molecules, since they share the basic structure of 1,25(OH) 2 D 3 but differ in the presence of a characteristic functional group (R) (Brown & Slatopolsky, 2008;Trump et al, 2010;Unten et al, 2004) (Figure 2).…”

“…19-nor-Vit D compounds are Vit D analogs in which the ring A methylene group on C-19 is replaced with two hydrogen atoms (Chen & Kittaka, 2011) (Figure 2). MART-10 (19-nor2a-(3-hydroxypropyl)-1a,25(OH) 2 D 3 ) and 25(OH) 2 D 3 ) are two new synthetic C2-substituted 19-nor-1a,25(OH) 2 D 3 analogs of Vit D that have negligible effects on calcium plasma levels and that appear to be effective in the prevention and treatment of prostate cancer (Chen & Kittaka, 2011;Kittaka et al, 2012).…”

“…MART-10 (19-nor2a-(3-hydroxypropyl)-1a,25(OH) 2 D 3 ) and 25(OH) 2 D 3 ) are two new synthetic C2-substituted 19-nor-1a,25(OH) 2 D 3 analogs of Vit D that have negligible effects on calcium plasma levels and that appear to be effective in the prevention and treatment of prostate cancer (Chen & Kittaka, 2011;Kittaka et al, 2012). In vitro studies on the HL-60 cell line showed that compared with 1,25(OH) 2 D 3 , MART-10, and MART-11 are endowed with a different degree of binding affinity for VDR (100 and 3%).…”

“…These findings demonstrated that MART-10 is biologically active in vivo and may be of clinical usefulness in treating prostate cancer. Therefore, the induction of the CYP24A1 gene was used as an index for evaluating the biological potency of new Vit D analogs (Chen & Kittaka, 2011). These studies additionally highlighted the fact that MART-10 induced CYP24A1 gene expression at a lower concentration with a longer duration compared with 1a,25(OH )2 D 3 , suggesting that MART-10 is less susceptible to CYP24A1 degradation (Flanagan et al, 2009;Iglesias-Gato et al, 2011).…”