A DUAL BLOCK TO CELL-CYCLE PROGRESSION IN HL-60 CELLS EXPOSED TO ANALOGS OF VITAMIN-D-3

The physiologically active form of vitamin D-3, 1,25-dihydroxy-vitamin D-3 (1,25(OH)(2)D-3), induces differentiation of several types of mye loid leukaemia cells. The acquisition of monocyte-like phenotype is ac companied by slower progression through the cell cycle, and G(1) block has been reported to be the basis of this effect. It is shown here th at human promyelocytic leukaemia HL60 cells treated with analogues of vitamin D-3 which are potent inducers of monocytic differentiation hav e an additional cell cycle block. Exposure to 10(-7)M 1,25(OH)(2)D-3 o r 1,25-(OH)(2)-16-ene-D-3 resulted in monocytic differentiation and th e expected G(1) block evident at approximately 48 h in a rapidly diffe rentiating variant of HL60 cells (HL60-G), and at 96 h in the more slo wly differentiating HL60-240 cells. In addition, a G(2)+M block was no ted at approximately 72 h in HL60-G and HL60-240 cells. Exposure to vi tamin D-3 analogues also markedly increased the number of dikaryons, s uggesting that cytokinesis was impaired more than karyokinesis. Treatm ent with a third analogue 25-hydroxy-16,23-diene-D-3 produced little d ifferentiation and had minimal effects on the cell cycle parameters. T hese findings indicate that vitamin D-3 analogues regulate cell prolif eration by control of the transition of G(1) and G(2)+M phases, remini scent of the cdc2/CDK2 type of cell cycle control.