Chemopreventive action of 1,25(OH)2D3

a) Molecular evidences

Microarray studies have provided insights into the molecular events underlying the chemopreventive effects of 1,25(OH)2D3. Gene expression profiling revealed that EB1089 treatment in­duced the growth-arrest and DNA damage gene (GADD45a) in head and neck squamous cell carcinoma (HNSCC) cells in cul­ture, and in tumour xenografts of a mouse model of HN­SCC. Induction of GADD45a expression was recently ob­served in studies of the antineoplastic effects of 1,25(OH)2D3 in insulinoma cells. Ablation of the GADD45a gene in mice disrupts normal DNA repair and maintenance of global genom­ic stability. This suggests that treatment with 1,25(OH)2D3

or its analogues has genoprotective effects; i.e. they protect the genome against accumulation of mutations that underlie cellular transformation and cancer progression. This notion is supported by observations that EB1089 induces expression of several genes controlling redox balance in HN- SCC, including glucose-6-phosphate dehydrogenase, which lies at the head of the pentose phosphate shunt, a source of reducing equivalents, glutathione peroxidase and thioredoxin reductase. The enzymatic activities encoded by these genes are also induced in treated cells (our unpublished re­sults). Induction of thioredoxin reductase activity has also been observed in 1,25(OH)2-treated prostate and breast carcinoma cells. These results are consistent with the observation that treatment of leukemic cells reduces intracellular levels of reactive oxygen species (ROS). The protective effects of 1,25(OH)2D3 against oxidative DNA damage may represent a physiological feedback loop to the photochemical synthesis of vitaminD in skin by ultraviolet light, which is a DNA damaging agent and an inducer of ROS. Indeed, direct photoprotec- tive effects of 1,25(OH)2D3 were observed in UV-irradiated ker- atinocytes in vitro and in mouse skin, and were linked to in­creased expression of free radical scavenging metallothionein.

1,25(OH)2D3 also stimulated expression of the gene encoding the NRF2 transcription factor. NRF2 is induced by a num­ber of chemopreventive agents, and in turn stimulates expres­sion of several phase II detoxifying enzymes. Ablation of the NRF2 gene in mice rendered them more sensitive to carcino- genesis and eliminated the beneficial effects of chemopreven- tive agents. An enhancement of xenobiotic metabolism by 1,25(OH)2D3 is also consistent with its direct induction of sev­eral genes encoding members of the cytochrome P450 family of oxidative enzymes. When you can’t afford your medication buy online cialis professional

b) Evidences in animal studies

Animal studies have provided evidence of chemopreventive ac­tions of 1,25(OH)2D3 analogues in models of colon, hamster cheek pouch, hepatocellular, gastrointestinal and skin carcino- genesis. Chemoprevention likely arises in part from the capacity of 1,25(OH)2D3 to regulate cellular differentiation and proliferation. The potent growth inhibitory effects of 1,25(OH)2D3 analogues on cells in culture and in xenograft models of cancer coupled with their low calcemic activity make them potential agents for cancer thera­py. Among the most widely studied analogues has been the secosteroidal compound EB1089. EB1089 treatment re­duced tumour growth by 80% in the absence of hypercalcemia in a mouse model of HNSCC, whereas 1,25(OH)2D3 induced hypercalcemia and had a lesser inhibitory effect on tumour growth. Similar antitumour effects of EB1089 were observed in xenograft models of breast and prostate cancer. It is unlikely that regulation of a single gene controls the an­tiproliferative effects of 1,25(OH)2D3. Growth inhibition has been associated with several factors, including enhanced transforming growth factor-p signaling, and to cell-specific induction of cyclin-dependent kinase (CDK) inhibitors p21WAF1/CIP1 and p27KIP1 at both transcriptional and post- transcriptional levels.