Journal Article

Early Growth Inhibition Is Followed by Increased Metastatic Disease with Vitamin D (Calcitriol) Treatment in the TRAMP Model of Prostate Cancer

Ajibade, Adebusola Alagbala, Johnson, Candace S., Foster, Barbara A., Gillard, Bryan, Karasik, Ellen, Kirk, Jason S., Moser, Michael T., Trump, Donald L.

2014

Overview

The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol) has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW), were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg), or QW (50 µg/kg) were administered to 4 week-old TRAMP mice intraperitoneal (i.p.) 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW) and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW). However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086), and reduced tumor proliferation (p = 0.0467). By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823). Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20-25 weeks-of-age)(p = 0.0003). Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenocarcinoma / Adenocarcinoma - drug therapy / Adenocarcinoma - epidemiology / Adenocarcinoma - secondary / Analysis / Androgens / Animals / Apoptosis / Biology / Blotting, Western / Cadherin / Cadherins / Calcitriol / Cancer / Cancer metastasis / Cancer research / Castration / Cell cycle / Cell Differentiation - drug effects / Cell growth / Cell Proliferation - drug effects / Dihydroxyvitamin D3 / Disease Models, Animal / E-cadherin / Epidemiology / Genetic engineering / Humans / Immunoenzyme Techniques / Incidence / Laboratory animals / Male / Medical research / Medical treatment / Medicine / Metabolites / Metastases / Metastasis / Mice / Mice, Inbred C57BL / Mice, Transgenic / Mortality / Pharmacology / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - epidemiology / Prostatic Neoplasms - pathology / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - epidemiology / Prostatic Neoplasms, Castration-Resistant - secondary / Statistics / Studies / Transgenic / Tumor Cells, Cultured / Tumors / Vitamin D / Vitamin D - analogs & derivatives / Vitamin D - pharmacology / Vitamin D3