seocalcitol and Neoplasms

It is well established that the metabolically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) plays a key role in the establishment and maintenance of the calcium metabolism in the body. In addition to this classic effect of 1alpha,25(OH)2D3, substantial evidence has emerged demonstrating that 1alpha,25(OH)2D3 is able to regulate cell growth and differentiation in a number of different cell types, including cancer cells. However, the clinical usefulness of 1alpha,25(OH)2D3 is limited by its tendency to cause hypercalcaemia. Much effort has therefore been directed to identifying new vitamin D analogues with potent cell regulatory effects, but with weaker effects on the calcium metabolism than those of 1alpha,25(OH)2D3. One of these new synthetic analogues is Seocalcitol (EB 1089). Despite being 50-200 times more potent than 1alpha,25(OH)2D3 with respect to regulation of cell growth and differentiation in vitro as well as in vivo, EB 1089 displays a reduced calcaemic activity in vivo compared to that of 1alpha, 25(OH)2D3. These characteristics make EB 1089 a potentially useful compound for the treatment of cancer. Recent clinical evaluation of EB 1089 has focused mainly on establishing a maximum tolerated dose in cancer patients. Early results confirm that the low calcaemic activity observed in animals can be reproduced in the clinic. Furthermore, EB 1089 has been shown to induce regression of tumours, especially in hepatocellular carcinoma where complete remission has been obtained. In conclusion, the development of EB 1089 as an anti-cancer drug holds promise. However, its final evaluation must await the completion of ongoing controlled clinical trials.

Topics: Animals; Antineoplastic Agents; Apoptosis; Calcitriol; Cell Cycle; Cell Differentiation; Drug Design; Humans; Neoplasms

Treatment of cancer cells with 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)] or its analogs induces growth arrest and expression of the cyclin-dependent kinase inhibitor p27(KIP1). Although 1,25(OH)(2)D(3) transiently enhances p27(kip1) gene transcription in some cells, its effects on p27(KIP1) protein levels are generally more gradual and sustained. This suggests that 1,25(OH)(2)D(3) treatment may be stabilizing p27(KIP1) protein, which is sensitive to modification by the SCF(SKP2) protein ubiquitin ligase and proteosomal degradation. Here, we show that treatment of AT-84 head and neck squamous carcinoma cells with the 1,25(OH)(2)D(3) analog EB1089 increases p27(KIP1) protein levels without significantly affecting expression of its mRNA. EB1089 treatment repressed expression of mRNAs encoding the F-box protein p45(SKP2), a marker of poor head and neck cancer prognosis, and the cyclin kinase subunit CKS1, which is essential for targeting p45(SKP2) to p27(KIP1). This coincided with a reduction of total p45(SKP2) protein, and p45(SKP2) associated with p27(KIP1). Consistent with these findings, turnover of p27(KIP1) protein was strongly inhibited in the presence of EB1089. A similar reduction in p45(SKP2) expression and stabilization of p27(KIP1) protein was observed in 1,25(OH)(2)D(3)-sensitive UF-1 promyelocytic leukemia cells, which also respond by transiently increasing p27(kip1) gene transcription. Our results reveal that 1,25(OH)(2)D(3) analogs increase levels of p27(KIP1) in different cell types by inhibiting expression of SCF(SKP2) subunits and reducing turnover of p27(KIP1) protein.

Topics: Animals; Antineoplastic Agents; Blotting, Northern; Calcitriol; Carcinoma, Squamous Cell; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Drug Stability; Enzyme Inhibitors; G1 Phase; Gene Expression; Head and Neck Neoplasms; Humans; Immunosorbent Techniques; Mice; Neoplasms; Resting Phase, Cell Cycle; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; S-Phase Kinase-Associated Proteins; Tumor Cells, Cultured; Tumor Suppressor Proteins