Vitamin D3 analogs and their 24-Oxo metabolites equally inhibit clonal proliferation of a variety of cancer cells but have differing molecular effects
✍ Scribed by Moray J. Campbell; G. Satyanarayana Reddy; H. Phillip Koeffler
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 183 KB
- Volume
- 66
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
The seco-steroid hormone, 1a,25 dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) binds to a specific nuclear receptor that acts as a ligand-inducible transcription factor. The resulting genomic effects include partial arrest in G 0 /G 1 of the cell cycle and induction of differentiation; these effects have been observed in various types of cancer. Recently, we produced enzymatically the natural 24-oxo metabolites of 1a,25(OH) 2 D 3 and two of its potent synthetic analogs (1a,25-(OH) 2 -16-ene-D 3 and 1a,25-(OH) 2 -20-epi-D 3 ) using a rat kidney perfusion system. We have found that the 24-oxo metabolites of both 1a,25(OH) 2 D 3 and its analogs have either the same or greater antiproliferative activity against various cancer cells as their parental compounds. Notably, two cell lines (DU-145 (prostate cancer) and MDA-MB-436 [breast cancer]) that were extremely resistant to the antiproliferative effects of vitamin D 3 analogs displayed greater sensitivity towards the 24-oxo metabolite of the vitamin D 3 analog. Similarly, the 24-oxo metabolites had the capacity to induce differentiation and apoptosis and to diminish the proportion of cells in S phase. Most interestingly, while the analog 1a,25(OH) 2 -20-epi-D 3 induced expression of BRCA1 in MCF-7 breast cancer cells; its 24-oxo metabolite dramatically suppressed BRAC1 expression. Thus, we have shown for the first time that the various biological activities produced by the hormone 1a,25(OH) 2 D 3 and some of its analogs may represent a combination of actions by the hormone 1a,25(OH) 2 D 3 and its natural 24-oxo metabolites.