Growth inhibition and differentiation induction in human monoblastic leukaemia cells by 1alpha-hydroxyvitamin D derivatives and their enhancement by combination with hydroxyurea

Abstract

The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a potent inducer of differentiation in myeloid leukaemia cells, but its clinical use is limited because of its hypercalcaemic activity. We examined the ability of 1,25(OH)2D3 in combination with several anti-cancer drugs to inhibit the proliferation of, and induce differentiation in, human monoblastic leukaemia U937 cells. Hydroxyurea (HU), cytarabine and camptothecin showed effective synergism with 1,25(OH)2D3 with regard to growth inhibition, while daunorubicin and etoposide had only modest synergistic effects. HU and cytarabine effectively enhanced nitroblue tetrazolium-reducing activity induced by 1,25(OH)2D3. HU also enhanced the morphological maturation and expression of CD11b and CD14 in cells treated with 1,25(OH)2D3. Among the anti-cancer drugs examined, HU had the greatest synergistic effects with 1,25(OH)2D3 with regard to growth inhibition and differentiation induction in U937 cells. HU also enhanced the differentiation of other myeloid leukaemia HL-60, ML-1, THP-1, P39/TSU, P31/FUJ and NB4 cells induced by 1,25(OH)2D3 and that of U937 cells induced by 24-epi-1,25(OH)2D2 and 1,25(OH)2D7. Interestingly, 1alpha(OH)D derivatives (1alpha-hydroxyvitamin D3, D2, D4 and D7) effectively induced the differentiation of monoblastic leukaemia U937, P39/TSU and P31/FUJ cells. HU also enhanced the growth inhibition and differentiation of U937 cells induced by 1alpha(OH)D derivatives. As 1alpha(OH)D derivatives preferentially act on monocytic cells, they may be useful in the treatment of acute monocytic leukaemia, both alone and in combination with HU.