The effects of 1 alpha,24(S)-dihydroxyvitamin D-2 analog on cancer cell proliferation and cytokine expression

It is well established that 1 alpha ,25-dihydroxyvitamin D-3 (1 alpha ,25(O H)(2)D-3). the active metabolite of vitamin D, plays a role in regulating p roliferation and differentiation of cells, in addition to its classic funct ion in mineral homeostasis. Recent studies have also provided evidence for the involvement of 1 alpha ,25(OH)(2)D-3 in regulating the immune system. H owever, therapeutic application of 1 alpha ,25(OH)(2)D-3 to hyperproliferat ive diseases such as cancer, or for immunologic purposes, is thwarted by it s hypercalcemic activity. In order to overcome this obstacle, analogs of 1 alpha ,25(OH)(2)D-3 have been produced that exhibit decreased hypercalcemic activity while retaining the growth and immunologic regulating properties. In the present study, the efficacy of 1 alpha ,24(S)-dihydroxyvitamin D-2 (1 alpha ,24(S)(OH)(2)D-3), a vitamin D-2 analog, in restraining cell proli feration was compared to that of 1 alpha .25(OH)(2)D-3. In parallel studies , cancer cell lines were grown in increased concentrations (10(-10)-10(-7) M) of each compound for various incubation periods (1-4 days). Growth was a ssessed by measuring [H-3]thymidine incorporation. The results revealed tha t 1 alpha ,24(S)(OH)(2)D-2 significantly inhibits proliferation to an exten t similar to that observed for 1 alpha ,25(OH)(2)D-3. Moreover, incubating the human leukemia cell line, HL-60, with 1 alpha ,24(S)(OH)(2)D-3 resulted in an induction of differentiation of these promyelomonocyte cells into mo nocyte-macrophage-like cells, in a manner similar to that observed with 1 a lpha ,25(OH)(2)D-3. Using a Western procedure, it was also shown that 1 alp ha ,24(S)(OH)(2)D-2 like 1 alpha 25(OH)(2)D-3 enhances the expression of vi tamin D receptors (VDR) in the rat osteosarcoma cell line, ROS 17/2.8. The expression of tumor necrosis factor (TNF) alpha (TNF-alpha) in human perito neal macrophages (HPM) obtained from uremic patients treated with continuou s ambulatory peritoneal dialysis (CAPD) was found to be regulated by 1 alph a ,25(OH)(2)D-3 as well as by 1 alpha ,24(S)(OH)(2)D-3. Incubations of HPM with 1 alpha ,25(OH)(2)D-3 or 1 alpha ,24(S)(OH)(2)D-3, have inhibited the expression of TNF-alpha on both mRNA and protein levels. These results sugg est that 1 alpha ,25(OH)(2)D-3 has a role in controlling the rate of inflam mation in the peritoneal cavity of CAPD treated patients. Since 1 alpha ,24 (S)(OH)(2)D-3 does not cause hypercalcemia, the present results encourage t he possible use of this vitamin D-2 analog in the treatment of cancer and h yper-inflammatory diseases. (C) 2001 Elsevier Science Inc. All rights reser ved.