1-25-dihydroxy-16-ene-vitamin-d3 and Breast-Neoplasms

The seco-steroid hormone, 1 alpha, 25 dihydroxyvitamin D3 (1 alpha,25(OH)2D3) binds to a specific nuclear receptor that acts as a ligand-inducible transcription factor. The resulting genomic effects include partial arrest in G0/G1 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 1 alpha,25(OH)2D3 and two of its potent synthetic analogs (1 alpha,25-(OH)2-16-ene-D3 and 1 alpha,25-(OH)2-20-epi-D3) using a rat kidney perfusion system. We have found that the 24-oxo metabolites of both 1 alpha,25(OH)2D3 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 D3 analogs displayed greater sensitivity towards the 24-oxo metabolite of the vitamin D3 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 1 alpha,25(OH)2-20-epi-D3 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 1 alpha,25(OH)2D3 and some of its analogs may represent a combination of actions by the hormone 1 alpha,25(OH)2D3 and its natural 24-oxo metabolites.

Topics: Apoptosis; bcl-2-Associated X Protein; BRCA1 Protein; Breast Neoplasms; Cadherins; Calcitriol; Cell Cycle; Cell Cycle Proteins; Cell Division; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; HL-60 Cells; Humans; Male; Microtubule-Associated Proteins; Neoplasms; Prostatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Tumor Suppressor Proteins

[3H]thymidine incorporation and DNA content were used to investigate the antiproliferative effects of 1,25(OH)2D3 and four analogues [16-ene-1,25(OH)2D3 (16-ene)]; 16-ene,23-yne-1,25(0H)2,D3; EB1089; and 22 oxa-1,25(OH)2D3] on MCF-7, BT-474, and MDA-MB-453 breast cancer cell lines. 1,25(OH)2D3 and the analogues elicited a biphasic response from MCF-7 and BT-474 estrogen receptor (ER)-positive cells, in the presence of estradiol (E2), with lower doses (between 10(-12) and 10(-10) M) tending to stimulate proliferation and higher doses (between 10(-9) and 10(-6) M) inhibiting proliferation by as much as 65%. In the absence of E2, the stimulatory effect was abrogated. Proliferation of MDA-MB-453, estrogen receptor-negative (ER-) cells, was stimulated by these compounds only at 10(-12) M, and inhibited by all higher doses, by as much as 83%. All three cell lines were shown to be vitamin D receptor (VDR) positive, and 1,25(OH)2D3 and all four analogues bound to the VDR with high affinities in each cell line. The antiestrogen ICI 164,384 inhibited the proliferation of all three cell lines. ICI 164,384 at 10(-8) M in combination with 1,25(OH)2D, or EB1089 converted biphasic response of the ER+ cells to one resembling the response of the ER- cells, by eliminating the stimulatory response elicited by 1,25(OH)2D3 at low doses and enhancing the antiproliferative effects of higher doses by as much as 1000-fold. These data are consistent with the hypothesis that E2 in the ER+ cells blocks the antiproliferative effects of the analogues and suggest the potential usefulness of combined antiestrogen and 1,25(OH)2D3 analogues in ER+ breast tumors, whereas 1,25(OH)2D3 analogues alone might suffice in ER- breast tumors.

Topics: Antineoplastic Agents; Breast Neoplasms; Calcitriol; Cell Division; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Estradiol; Estrogen Antagonists; Female; Humans; Neoplasm Proteins; Polyunsaturated Alkamides; Receptors, Calcitriol; RNA, Messenger; Tumor Cells, Cultured