19-nor-hexafluoride analogue of vitamin D3: a novel class of potent inhibitors of proliferation of human breast cell lines.
Breast cancer cells express vitamin D3 receptors and 1,25-dihydroxyvitamin D3 suppressed growth of these cells. We have synthesized six novel vitamin D3 analogues to identify those with expanded capacity to inhibit the proliferative ability of breast cancer cells. These analogues incorporated many of the structural motifs shown previously to have antiproliferative activity in several cell types. Six breast cancer cell lines were used as targets. Dose-response studies showed that each of the analogues had antiproliferative activities, and LH [1,25-(OH)2-16-ene-23-yne-26,27-F6-19-nor D3] was the most potent analogue, suppressing at 10(-11) M greater than 50% clonal proliferation (ED50) of the MCF-7 and SK-BR-3 breast cancer cells, increasing the proportion of MCF-7 cells in the G0-G1 phase, and decreasing those in the S phase of the cell cycle. Pulse-exposure studies showed that a 3-day exposure to LH (10(-7) M) in liquid culture was adequate to achieve a 50% inhibition of MCF-7 clonal growth in soft agar in the absence of the analogue, suggesting that the growth inhibition mediated by LH is irreversible. The cyclin-dependent kinase inhibitor known as p27Kip1 helps regulate the cell cycle and can mediate growth arrest in response to extracellular growth inhibitors. The analogue LH (10(-7) M) induced elevated expression of p27Kip1 in MCF-7 and SK-BR-3 cells. Taken together, these results indicate that LH is an extremely potent vitamin D3 analogue markedly inhibiting clonal growth of MCF-7 and SK-BR-3 cells with concomitant cell cycle arrest at G0-G1 and increased expression of p27Kip1. Compound LH is worthy of in vivo analysis for possible future clinical trials.
Koike
M
M
Division of Hematology/Oncology, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA.
Elstner
E
E
Campbell
M J
MJ
Asou
H
H
Uskokovic
M
M
Tsuruoka
N
N
Koeffler
H P
HP
D000970:Antineoplastic Agents / Q000633:toxicity*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C108274:19-nor-hexafluoride vitamin D3; D000970:Antineoplastic Agents; D002762:Cholecalciferol