Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol) treatment in the TRAMP model of prostate cancer.

Abstract

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.

• Authors: Adebusola Alagbala Ajibade, Jason S Kirk, Ellen Karasik, Bryan Gillard, Michael T Moser, Candace S Johnson, Donald L Trump, Barbara A Foster
• Journal: PloS one (PLoS One) Vol. 9 Issue 2 Pg. e89555 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24586868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• dihydroxy-vitamin D3
• Vitamin D

Topics

• Adenocarcinoma (drug therapy, epidemiology, secondary)
• Animals
• Blotting, Western
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Humans
• Immunoenzyme Techniques
• Incidence
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Prostatic Neoplasms (drug therapy, epidemiology, pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, epidemiology, secondary)
• Tumor Cells, Cultured
• Vitamin D (analogs & derivatives, pharmacology)