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Vitamin D 3 analogs and their 24‐Oxo metabolites equally inhibit clonal proliferation of a variety of cancer cells but have differing molecular effects
Author(s) -
Campbell Moray J.,
Reddy G. Satyanarayana,
Koeffler H. Phillip
Publication year - 1997
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(19970901)66:3<413::aid-jcb13>3.0.co;2-f
Subject(s) - metabolite , calcitriol receptor , cancer cell , steroid hormone , cell culture , cell growth , growth inhibition , chemistry , cell cycle , biological activity , biochemistry , biology , hormone , cancer , in vitro , apoptosis , receptor , genetics
The seco‐steroid hormone, 1α,25 dihydroxyvitamin D 3 (1α,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 1α,25(OH) 2 D 3 and two of its potent synthetic analogs (1α,25‐(OH) 2 ‐16‐ene‐D 3 and 1α,25‐(OH) 2 ‐20‐ epi ‐D 3 ) using a rat kidney perfusion system. We have found that the 24‐oxo metabolites of both 1α,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 1α,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 1α,25(OH) 2 D 3 and some of its analogs may represent a combination of actions by the hormone 1α,25(OH) 2 D 3 and its natural 24‐oxo metabolites. J. Cell. Biochem. 66:413–425, 1997. © 1997 Wiley‐Liss, Inc.