VITAMIN-D-3 DERIVATIVES AND BREAST-TUMOR CELL-GROWTH - EFFECT ON INTRACELLULAR CALCIUM AND APOPTOSIS

Vitamin-D-3 derivatives are now well-recognized growth inhibitors of numerous tumoral cells and in particular breast-cancer cells. However, the mechanisms by which they operate are not well established. Among the wide range of physiological and biological functions of vitamin-D-3 derivatives, the best described include their action on calcium homeostasis. In this study, we sought to establish whether the effects of vitamin-D-3 derivatives on breast-cancer cell growth may be in part related to intracellular calcium modulation and induction of apoptosis. To address these questions, we used, in addition to 1,25(OH)(2)D-3, the active metabolite of vitamin D-3, a non-calcemic 1,25(OH)(2)D-3 derivative: Ro 23-7553 [16-ene-23-yne-1,25(OH)(2)D-3], which in our hands was more potent than the parent compound in inhibiting breast-cancer cell growth. We showed that the efficiency of both compounds in growth inhibition was higher in the estradiol-receptor-positive-breast-tumor MCF-7 cells than in the estradiol-receptor-negative MDA-MB 231 cells. In MCF-7 cells in particular, important modifications of intracellular calcium related to the emptying of intracellular pools were observed. The depletion of Ca++ from intracellular stores was followed by the induction of apoptosis. Such a phenomenon was never observed in MDA-MB 231 cells. Our results suggest that the action of vitamin-D-3 derivatives on the depletion of calcium stores, which was more significant in MCF-7 than in MDA-MB 231 cells, may induce apoptosis in the former cells and account for the high efficiency of vitamin-D-3 derivatives on growth inhibition of MCF-7 breast-tumor (C) 1995 Wiley-Liss, Inc.