Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Abstract

Today, it is well established that besides playing a crucial role in the establishment and maintenance of the calcium homeostasis in the body, the active form of vitamin D, 1,25(OH)2D3, also acts an effective regulator of cell growth and differentiation in a number of different cell types, including cancer cells. This has led to an increased interest in using 1,25(OH)2D3 in the treatment or prevention of cancer patients and to a substantial number of studies investigating the effect of 1,25(OH)2D3 on cancer cells. The results are encouraging, but clearly demonstrate that the therapeutic window of 1,25(OH)2D3 is extremely narrow due to the calcemic adverse effects of this compound. Much effort has consequently been directed into identifying vitamin D analogs with potent cell regulatory effects but with weaker effects on the calcium metabolism than those of 1,25(OH)2D3. In an attempt to clarify the mechanisms implicated in the cell regulatory effects of 1,25(OH)2D3 and eventually facilitate the process of developing new specific vitamin D analogs, numerous investigations have been carried out with 1,25(OH)2D3 and its analogs. The present review will focus on the results obtained in these studies and describe some of the synthetic analogs, which have shown to be of particular interest in relation to cancer.

Plasma 25‐hydroxyvitamin D and premenopausal breast cancer risk in a German case‐control study

“…the bcl-2 family, insulin-like growth factor I/II, and tumor necrosis factor-alpha. 2,31,32 As these general mechanisms of cellular growth equally apply to premenopausal and postmenopausal women, a protective effect of vitamin D on both premenopausal and postmenopausal breast cancer is likely.…”

Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery

“…Apart from the established role of vitamin D 3 in the regulation of calcium homeostasis, numerous studies have shown the metabolically active form of vitamin D 3 , 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], to have strong growth-inhibitory effects on a variety of tumor cell lines (1). Because hypercalcemia limits the concentrations of vitamin D 3 achievable in the clinic, several vitamin D 3 analogues, such as EB 1089 (seocalcitol), have been synthesized with reduced hypercalcemic activity.…”

“…Previous work from this laboratory has shown that vitamin D 3 [1,25(OH) 2 D 3 ; cholecalciferol] and vitamin D 3 analogues, such as EB 1089 and ILX23-7553, enhance the response to both ionizing radiation (IR) and the antitumor drug, Adriamycin, in breast tumor cells (2 -5); for IR, the effects of EB 1089 were also shown to occur in tumor cell xenografts (6). These findings are consistent with previous work by several research groups showing that vitamin D 3 and/or its analogues can potentiate the sensitivity to chemotherapeutic drugs in various experimental tumor systems (7 -12).…”

“…Multiple mechanisms have been shown to mediate the genomic, receptor-mediated based actions of vitamin D 3 and its analogues in the tumor cell (1,14). The current studies were done in an effort to identify the specific signaling pathways responsible for the observed interactions of vitamin D 3 and its analogues with radiation.…”

1α,25-Dihydroxyvitamin D3 (calcitriol) and its analogue, 19-nor-1α,25(OH)2D2, potentiate the effects of ionising radiation on human prostate cancer cells

“…Consequently, many synthetic analogues of 1,25(OH) 2 D 3 have been developed with the goal of developing analogues that exhibit similar or enhanced growth-inhibitory and antimetastatic properties with reduced calcaemic effects (Schwartz and Hulka, 1990) (see also Hansen et al (2001) (Chen et al, 2000).…”