Vitamin D-Prostaglandin Interactions and Effects in Prostate Cancer
Abstract
1,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D3 is a hormone with anti-proliferative and prodifferentiation effects in prostate cancer (PCa) cells. Our ultimate goal is to identify novel therapeutic targets for the treatment of PCa with calcitriol. Previous to this study, we have used cDNA microarray analysis of established human PCa cell lines identifying, among others, the regulation of genes implicated in prostaglandin (PG) bioactivity. PGs are implicated in the development and progression of PCa, tumor invasiveness and tumor grade. We found that calcitriol down-regulates the expression of cyclooxygenase-2 (COX-2), enzyme that initiates PG synthesis, and up-regulates the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) involved in the first step in PG inactivation. In this project we analyze these two novel target genes of calcitriol. In this project we found that calcitriol reduces the expression of COX-2 mRNA and protein and up-regulates 15-PGDH mRNA and protein. We also found that the combined treatment of LNCaP and PC-3 cells with calcitriol and COX inhibitors mediate synergistic growth inhibition, allowing the use of reduced doses of both drugs that still resulted in enhanced anti-proliferative activity. The actions of calcitriol to reduce COX-2 expression and to induce 15-PGDH availability would potentially constitute a pathway to reduce and/or remove active PGs thereby diminishing PCa proliferation. These findings suggest that therapy combining calcitriol and COX-2 inhibitors will increase efficacy while decreasing side-effects. We strongly believe that the major contribution and significance of this project is to pave the way in the designing of new therapeutic approaches for PCa. We propose that the combination of these already approved drugs can be brought to a clinical trial swiftly.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2006
- Accession Number
- ADA463443
Entities
People
- Jacqueline Moreno
Organizations
- Stanford University