The effects of
1,25-dihydroxyvitamin D3 (
1,25(OH)2D3) and four novel synthetic analogues (
EB1089,
KH1060,
KH1230 and CB1093) on
IGF-I-stimulated growth of MCF-7 human
breast cancer cells have been determined. A significant time- and dose-dependent inhibition of
IGF-I-stimulated cell growth was seen with
EB1089, such that after 7 days of treatment with 10(-8) M
EB1089, the mitogenic effect of
IGF-I (30 ng/ml) was negated. Comparison with
1,25(OH)2D3 showed the synthetic analogues to be more potent. The anti-oestrogen
ICI 182,780 similarly inhibited
IGF-I-stimulated growth of these cells and in combination with
EB1089 exerted additional inhibitory effects.
Retinoids (
all-trans-retinoic acid or the isomer
9-cis-retinoic acid) were less effective in limiting MCF-7 cell responsiveness to
IGF-I but, in combination with
EB1089, a co-operative effect was achieved. Using radioligand-binding techniques, we observed that
1,25(OH)2D3 and
EB1089 down-regulated the levels of 125I-IGF-I binding to MCF-7 cell membranes. Scatchard analysis showed that
EB1089 decreased maximal binding approximately 2-fold.
Vitamin D derivatives were also demonstrated to reduce
IGF-I receptor expression in MCF-7 cells by Western analysis. Our findings demonstrate that
vitamin D derivatives limit responsiveness of MCF-7 cells to the mitogenic effects of
IGF-I, which may be mediated by reduction of
IGF-I receptor expression.