Early Growth Inhibition Is Followed by Increased Metastatic Disease with Vitamin D

• Published in: PloS one 2014-02, Vol.9 (2), p.e89555
• Main Authors: Ajibade, Adebusola Alagbala, Kirk, Jason S, Karasik, Ellen, Gillard, Bryan, Moser, Michael T, Johnson, Candace S, Trump, Donald L, Foster, Barbara A
• Format: Article
• Language: English
• Subjects: Analysis; Cancer metastasis; Cancer research; Genetic engineering; Prostate cancer; Statistics; Vitamin D
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089555

The active metabolite of vitamin D.sub.3, 1,25-dihydroxyvitamin D.sub.3 (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-1624F.sub.2 -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 [micro]g/kg), or QW (50 [micro]g/kg) were administered to 4 week-old TRAMP mice intraperitoneal (i.p.) 3x/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.