Enhancement of 1α, 25-dihydroxyvitamin D₃-induced differentiation of human leukaemia HL-60 cells into monocytes by parthenolide via inhibition of NF-κB activity

1. Transcription factors such as NF-κB provide powerful targets for drugs to use in the treatment of cancer. In this report parthenolide (PT), a sesquiterpene lactone of herbal remedies such as feverfew (Tanacetum parthenium) with NF-κB inhibitory activity, markedly increased the degree of human leukaemia HL-60 cell differentiation when simultaneously combined with 5 nM 1α, 25-dihydroxyvitamin D₃ (1, 25-(OH)₂D₃). PT by itself did not induce HL-60 cell differentiation. 2. Cytofluorometric analysis indicated that PT stimulated 1, 25-(OH)₂D₃-induced differentiation of HL-60 cells predominantly into monocytes. 3. Pretreatment of HL-60 cells with PT before the 1, 25-(OH)₂D₃ addition also potentiated the 1, 25-(OH)₂D₃-induced HL-60 cell differentiation in both a dose- and a time-dependent manner, in which the enhanced levels of cell differentiation closely correlated with the inhibitory levels of NF-κB binding activity by PT. 4. In contrast, santonin, a sesquiterpene lactone without an inhibitory activity of NF-κB binding to the κB sites, did not enhance the 1, 25-(OH)₂D₃-induced HL-60 cell differentiation. 5. In transfection experiments, PT enhanced 1, 25-(OH)₂D₃-induced VDRE-dependent promoter activity. Furthermore, PT restored 1, 25-(OH)₂D₃-induced VDRE-dependent promoter activity inhibited by TNF-α, an activator of NF-κB signalling pathway. 6. These results indicate that PT strongly potentiates the 1, 25-(OH)₂D₃-induced HL-60 cell differentiation into monocytes via the inhibition of NF-κB activity and provide evidence that inhibition of NF-κB activation can be a pre-requisite to the efficient entry of promyelocytic leukaemia cells into a differentiation pathway.