INDUCTION OF THE DIFFERENTIATION OF HL-60 PROMYELOCYTIC LEUKEMIA-CELLS BY CURCUMIN IN COMBINATION WITH LOW-LEVELS OF VITAMIN-D-3

Previous studies have shown that an antisense phosphorothioate oligonu cleotide to the Rel A subunit of NF-kappa B, as well as vitamin E and related antioxidants, significantly enhanced the differentiation of HL -60 leukemia cells when combined with low levers of 1 alpha,25-dihydro xyvitamin D-3 (vitamin D-3), an effect accompanied by a marked inhibit ion of the transcription factor, NF-kappa B. Curcumin, a potent inhibi tor of tumor promotion and of tumor cell growth, has also been shown t o have antioxidant properties and to inhibit NF-kappa B. To ascertain whether curcumin would also enhance the differentiation of HL-60 leuke mia cells produced by vitamin D-3, presumably by interfering with NF-k appa B activity, the effects of curcumin on the differentiation of HL- 60 cells produced by low levels of vitamin D-3 were measured. Curcumin used alone did not produce a significant degree of differentiation of HL-60 cells; however, this agent markedly enhanced the expression of differentiation markers induced by low levels of vitamin D-3. Curcumin also increased the differentiation of HL-60 cells when combined with vitamin D analogues (I,25 dihydroxy-16-ene-23-yne vitamin D-3 and 1,25 -dihydroxy-16-ene vitamin D-3) that share the receptor binding propert ies of vitamin D-3, whereas a vitamin D analogue (1,25-dihydroxy-16,23 -diene vitamin D-3) that caused significant calcium mobilization, but was less effective than vitamin D-3 in binding the receptor, did not c ause the differentiation of HL-60 cells in the presence or absence of curcumin. Several dietary compounds structurally related to curcumin ( i.e., caffeic acid, chlorogenic acid, and ferulic acid) did not increa se the differentiation of HL-60 cells produced by vitamin D-3. However , the more lipophilic ethyl esters of ferulic and caffeic acid were ca pable of inducing the differentiation of HL-60 cells, as well as enhan cing the maturation produced by vitamin D-3. Curcumin caused a marked reduction in NF-kappa B activity in nuclear extracts of HL-60 cells ex posed to this agent in the presence or absence of vitamin D-3, support ing the possibility that NF-kappa B may be a factor in the regulation of the state of differentiation of leukemia cells.