Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis

Abstract

Development of vitamin D analogs (deltanoids) as chemopreventive agents requires separation of desirable antiproliferative and pro-differentiating activities from the undesirable calcemic activity also found in the hormone calcitriol (1 alpha, 25-dihydroxyvitamin D(3)). Therefore, several conceptually new deltanoids were synthesized with modifications to the 1alpha- and/or 25-hydroxyl groups, positions traditionally considered essential for stimulating biological responses. In this study, 1 beta-hydroxymethyl-3-epi-25-hydroxyvitamin D(3), a non-calcemic CH(2) homolog of the natural hormone with antiproliferative activity in vitro, was ineffective as an inhibitor of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced induction of ornithine decarboxylase activity in mouse epidermis. However, a hybrid analog incorporating not only the calcemia-ablating 1 beta-hydroxymethyl alteration, but potentiating C,D ring 16-unsaturation and side chain 24,24-fluorination and 26, 27-homologation was found to be as effective as calcitriol. Several non-calcemic 24- or 25-t-butyl sulfones, some containing side chain fluorination but all lacking the 25-hydroxyl group, were also shown to be active in this assay. Three sulfones and the 1 beta-hydroxymethyl hybrid were evaluated as inhibitors of multistage carcinogenesis in mouse skin. Female CD-1 mice were initiated with a single dose of 7,12-dimethylbenz[a]anthracene and then promoted twice weekly for 20 weeks with TPA. Deltanoids were applied topically 30 min before TPA. Unlike calcitriol, none of the atypical deltanoids affected body weight gain in these animals. Minimal effects on urinary calcium excretion were observed following chronic treatment with these analogs. All deltanoids inhibited the incidence and multiplicity of papilloma formation, with the hybrid analog showing the greatest efficacy. With this deltanoid, tumor incidence was significantly reduced by 28% and tumor multiplicity by 63%. These results, coupled with the rich chemical diversity available in side chain sulfur-containing deltanoids, particularly when combined with A ring modifications such as 1 beta-hydroxylalkyl groups, provide important new advances in the fundamental understanding of chemical structure-biological activity relationships as well as more potent and safe vitamin D analogs for cancer chemoprevention and other medicinal uses.

Sex Differences in Photoprotective Responses to 1,25-Dihydroxyvitamin D3 in Mice Are Modulated by the Estrogen Receptor-β

“…Furthermore, the severity of both the suppression of contact hypersensitivity (CHS) and of photocarcinogenesis induced in mice by SSUV was reduced by topical vitamin D compounds [6,23,24]. These observations are consistent with the reported inhibition of chemical carcinogenesis by vitamin D [25,26] and the exacerbation of photocarcinogenesis in vitamin D receptor (VDR) knockout mice [27].…”

Systemic treatments with the low‐calcemic 1,25(OH)2D3 analogs JKF or QW increase both the morphological and biochemical responses to estradiol‐17β in rat tibiae

“…JKF and QW were synthesized by us (Fig. 1, [Kensler et al, 2000; Posner et al, 2004, 1998; Dixon et al, in press]). All other reagents were of analytical grade.…”

“…Using a rat model, we have reported [Somjen et al, 1995, 2000, 2001] that pretreatment with 1,25 or with vitamin D analogs upregulated the responsiveness and sensitivity to 17β‐estradiol (E 2 ) of skeletal cells in vitro or rat skeletal organs, but not in rat uterus in vivo [Kaye et al, 1990; Somjen et al, 1990; 1995; Fournier et al, 1996]. Pretreatment with 1,25 or less calcemic vitamin D analogs such as JK 1624 F 2 ‐2 (JKF), and QW 1624F 2 ‐2 (QW) [Kensler et al, 2000; Posner et al, 2004] upregulated the response of osteoblast‐like cells to E 2 as measured by the stimulation of the specific activity of creatine kinase BB (CK) [Somjen et al, 2000, 2001]. Furthermore, these analogs upregulated the responsiveness and sensitivity to E 2 in female rat epiphyses and diaphyses.…”

Antitumor Effects of Two Less-Calcemic Vitamin D Analogs (Paricalcitol and QW-1624F₂-2) in Squamous Cell Carcinoma Cells

“…QW is a novel fluorinated hybrid analog of calcitriol that is 100 times less calcemic and inhibits growth of melanoma cells [40]. QW inhibits skin carcinogenesis in vivo [41, 42] without inducing hypercalcemia [41]. Although QW has anticancer effects in vitro [43] and in vivo [42], its molecular effects on cell cycle, apoptosis and pro-survival signaling pathways have yet to be examined.…”