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

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Abstract
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. Cytofluorometric analysis indicated that PT stimulated 1,25‐(OH)2D3‐induced differentiation of HL‐60 cells predominantly into monocytes. 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. 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. 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. 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. British Journal of Pharmacology (2002) 135, 1235–1244; doi:10.1038/sj.bjp.0704573

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