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Enhancement of 1α,25‐dihydroxyvitamin D 3 ‐induced differentiation of human leukaemia HL‐60 cells into monocytes by parthenolide via inhibition of NF‐κB activity
Author(s) -
Kang S N,
Kim S H,
Chung S W,
Lee M H,
Kim H J,
Kim T S
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704573
Subject(s) - parthenolide , sesquiterpene lactone , cellular differentiation , chemistry , microbiology and biotechnology , inhibitory postsynaptic potential , activator (genetics) , cell , stereochemistry , apoptosis , biochemistry , biology , sesquiterpene , receptor , endocrinology , gene
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 n M 1α,25‐dihydroxyvitamin D 3 (1,25‐(OH) 2 D 3 ). PT by itself did not induce HL‐60 cell differentiation. Cytofluorometric analysis indicated that PT stimulated 1,25‐(OH) 2 D 3 ‐induced differentiation of HL‐60 cells predominantly into monocytes. Pretreatment of HL‐60 cells with PT before the 1,25‐(OH) 2 D 3 addition also potentiated the 1,25‐(OH) 2 D 3 ‐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) 2 D 3 ‐induced HL‐60 cell differentiation. In transfection experiments, PT enhanced 1,25‐(OH) 2 D 3 ‐induced VDRE‐dependent promoter activity. Furthermore, PT restored 1,25‐(OH) 2 D 3 ‐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) 2 D 3 ‐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