Elsevier

Steroids

Volume 66, Issues 3–5, 1 March–1 May 2001, Pages 293-300
Steroids

The role of vitamin D in prostate cancer

https://doi.org/10.1016/S0039-128X(00)00164-1Get rights and content

Abstract

Prostate cancer is the second leading cause of cancer deaths in men in the United States. Developing new treatment strategies is critical to improving the health of men. This article will be a general review of the field with a focus on research from our laboratory. Our research has focused on four areas in which we have pursued the possible use of 1α,25(OH)2D3 and its analogs to treat prostate cancer:

1) The ability of 1α,25(OH)2D3 to up-regulate androgen receptors in LNCaP human prostate cancer cells. The implications of this finding on 1α,25(OH)2D3’s ability to inhibit cell growth in vivo are unclear at present.

2) The reasons for an inability of 1α,25(OH)2D3 to inhibit DU 145 prostate cancer cell growth were explored. We found that combination of an imidazole drug, Liarozole, with 1α,25(OH)2D3 was capable of inhibiting DU 145 cell growth.

3) A number of low-calcemic vitamin D analogs exhibit potent anti-proliferative activity on prostate cancer cells. We have developed a novel approach using the yeast two-hybrid system to screen for potent analogs.

4) The results of a clinical trial of 1α,25(OH)2D3 treatment of patients with early recurrent prostate cancer. We provide preliminary evidence that 1α,25(OH)2D3 may be effective in slowing the rate of PSA rise in selected cases of prostate cancer.

In conclusion, we believe that 1α,25(OH)2D3 has a role in the treatment and/or prevention strategies being developed for prostate cancer. However, to increase antiproliferative potency without increasing side-effects, the use of less calcemic analogs appears to be the most reasonable approach.

Introduction

Cancer of the prostate (CaP) is a common lethal malignancy among men in Western Europe, Northern America and Australia. In the United States, approximately 8% of men may have clinically significant disease during their lifetime [1]. This year, 180 400 new cases of CaP are expected to be diagnosed and an estimated 31 900 Americans are expected to die of the disease [2]. As a consequence, CaP has become the second leading cause of cancer-related deaths in American men excluding lung cancer. This article will be a general review of vitamin D in CaP with a focus on research from our laboratory.

The etiology of CaP remains unclear. Epidemiologic studies have suggested that the cause of CaP is multifactorial and involves both genetic and environmental risk factors including age, race, family history, geography, and diet [3], [4], [5]. Approximately 10% of CaP cases are familial (hereditary). People with first degree relatives with CaP are at increased risk [6]. Some subjects in this subset of patients have been associated with genetic elements in chromosome 1 (HPC-1), BRCA1 and BRCA2 genes. However, the majority of CaP (90%) is sporadic, and a number of genes have been suggested to be associated with CaP risk [5]. They include genes encoding the androgen receptor (AR), the vitamin D receptor (VDR), the 5α-reductase enzyme, and the insulin-like growth factor (IGF) genes.

CaP is most often a disease of men over 50. The risk of developing CaP increases with age, and over 80% of CaP are found in men over the age of 65 [7]. African Americans have 50% higher chance of developing CaP than non-African Americans [8]. Mortality rates for CaP are high in North America and in Northwest Europe but appear to be lower in Africa and in Central and South America [4]. People who live in the northern latitudes have a higher risk than individuals that live closer to the equator. Diet appears to play an important role in CaP risk. Japanese men living in Japan have low risk of developing CaP, which increases upon immigration to the U.S. This increase in risk of CaP has been attributed to a change in diet [9]. Some of these risk factors may possibly be related to conditions that can alter vitamin D status as described below.

Schwartz and Hulka put forward the interesting hypothesis that vitamin D deficiency increases the risk of CaP [7]. Vitamin D is produced physiologically by UV irradiation through a precursor in the skin or it must be obtained from the diet. As men age they have decreased serum vitamin D levels, since the efficiency of previtamin D photoproduction decreases as a consequence of advancing age [10]. The degree of skin pigmentation (i.e. melanin content) also affects vitamin D synthesis in the skin [10]. Melanin protects the body from excess radiation by absorbing UV rays and, hence, the more melanin present in the skin, the less the UV radiation available for previtamin D synthesis. The basal levels of 25(OH)D3 are lower in young healthy blacks than seen in young healthy whites although blacks may have higher levels of 1α,25(OH)2D3 [11]. The mortality rates from CaP in the US are inversely proportional to incident ultraviolet radiation [4], which is essential for the cutaneous synthesis of the precursor to 1α,25(OH)2D3 [12]. Thus, the change in UV radiation exposure due to geographical residence can influence the amount of vitamin D synthesized in the skin. Japanese men usually consume a large amount of fish oil in their diet that contains a substantial amount of vitamin D. In a prospective study, Corder et al. found that in men greater than 57 years of age, serum levels of 1α,25(OH)2D3 were an important predictor of risk for the development of palpable and anaplastic CaP [13]. However, others have questioned these findings [14].

Section snippets

The role of androgens

Androgens play an important role in the development, growth and progression of CaP [3], [15]. A number of studies have indicated a correlation between serum testosterone levels and increased risk of CaP [16]. The AR is expressed in normal prostate and in most CaP specimens that have been evaluated [17]. Androgen promotes tumor growth and androgen ablation causes apoptosis of prostate epithelial cells [15].

Since CaP cells are dependent upon androgen stimulation for growth, castration was found

Vitamin D and the VDR

The hormonally active form of vitamin D is 1α,25(OH)2D3 (calcitriol). The production of 1α,25(OH)2D3 involves hydroxylation of vitamin D3 at the 25-position by the liver, and then 1-hydroxylation of 25-hydroxyvitamin D3 in the kidney. 1α,25(OH)2D3 together with parathyroid hormone are the primary regulators of mineral homeostasis and bone metabolism [12]. Calcitriol is best known for its role in intestinal calcium absorption and as a requirement to prevent rickets in children and osteomalacia

The role of VDR in CaP cells

The effect of 1α,25(OH)2D3 on human CaP cells was first demonstrated by in vitro studies. Ligand binding experiments showed that a number of established human CaP cell lines (LNCaP, PC-3, and DU 145) and primary culture of prostate epithelial cells (derived from normal, benign prostatic hyperplasia, and cancers) express functional VDR [29], [30], [31]. Like most other 1α,25(OH)2D3 target tissues, CaP cells contain VDR at 20–80 fmol/mg protein with an affinity of 0.1 nM. 1α,25(OH)2D3 at

Conclusions

1α,25(OH)2D3 and its analogs are capable of eliciting anti-proliferative responses through multiple mechanisms in human prostate cancer cells. Their anti-cancer properties suggest that these compounds may be therapeutically useful. The major side effect of vitamin D therapy is hypercalcemia and renal stone formation. This problem should be reduced with use of the less calcemic and more potent vitamin D analogs. In addition, combination therapy using vitamin D analogs together with other

Acknowledgements

This work is supported by NIH grant #DK42482, USAMRAA grant #DAMD 17–98-8556, and American Institute for Cancer Research grant #97A072 (D.F.).

References (56)

  • R.T Greenlee et al.

    Cancer Statistics, 2000

    CA Cancer J Clin

    (2000)
  • J.M Kozlowski et al.

    Carcinoma of the prostate

  • C.L Hanchette et al.

    Geographic patterns of prostate cancer mortalityEvidence for a protective effect of ultraviolet radiation

    Cancer

    (1992)
  • E Ruijter et al.

    Molecular genetics and epidemiology of prostate carcinoma

    Endocr Rev

    (1999)
  • C Woolf

    An investigation of the familial aspects of carcinoma of the prostate

    Cancer

    (1960)
  • G.G Schwartz et al.

    Is Vitamin D deficiency a risk factor for prostate cancer?

    Anticancer Res

    (1990)
  • L.Y Wu et al.

    Cancer rate differentials between blacks and whites in three metropolitan areasa 10-year comparison

    J Natl Med Assoc

    (1998)
  • W Haenszel et al.

    Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States

    J Natl Cancer Inst

    (1968)
  • M.F Holick

    Vitamin Dbiosynthesis, metabolism, and mode of action

  • N.H Bell et al.

    Evidence of alterations of the vitamin D-endocrine system in blacks

    J Clin Invest

    (1985)
  • D Feldman et al.

    Vitamin Dmetabolism and action

  • Corder EH, Guess HA, Hulka BS, Friedman GD, Sadler M, Vollmer RT, Lobaugh B, Drezner MK, Vogelman JH, Orentreich N....
  • M.M Braun et al.

    Prostate cancer and prediagnostic levels of serum vitamin D metabolites

    Cancer Causes Control

    (1995)
  • B.S Carter et al.

    Epidemiologic evidence regarding predisposing factors to prostate cancer

    Prostate

    (1990)
  • C Huggins et al.

    Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of the prostate gland

    Arch Surg

    (1941)
  • A.R Baker et al.

    Cloning and expression of full-length cDNA encoding human vitamin D receptor

    Proc Natl Acad Sci

    (1988)
  • R.M Evans

    The steroid and thyroid hormone receptor superfamily

    Science

    (1988)
  • M.R Haussler et al.

    The nuclear vitamin D receptorbiological and molecular regulatory properties revealed

    J Bone Mineral Res

    (1998)
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