Enhancement of 1 alpha,25-dihydroxyvitamin D(3)-induced differentiation of human leukaemia HL-60 cells into monocytes by parthenolide via inhibition of NF-kappa B activity.
1. Transcription factors such as NF-kappa B 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-kappa B inhibitory activity, markedly increased the degree of human leukaemia HL-60 cell differentiation when simultaneously combined with 5 nM 1 alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)). PT by itself did not induce HL-60 cell differentiation. 2. Cytofluorometric analysis indicated that PT stimulated 1,25-(OH)(2)D(3)-induced differentiation of HL-60 cells predominantly into monocytes. 3. 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-kappa B binding activity by PT. 4. In contrast, santonin, a sesquiterpene lactone without an inhibitory activity of NF-kappa B binding to the kappa B sites, did not enhance the 1,25-(OH)(2)D(3)-induced HL-60 cell differentiation. 5. 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-alpha, an activator of NF-kappa B signalling pathway. 6. 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-kappa B activity and provide evidence that inhibition of NF-kappa B activation can be a pre-requisite to the efficient entry of promyelocytic leukaemia cells into a differentiation pathway.
Kang
S N
SN
Immunology Laboratory, College of Pharmacy, Chonnam National University, Kwangju 500-757, Korea.
Kim
S H
SH
Chung
S W
SW
Lee
M H
MH
Kim
H J
HJ
Kim
T S
TS
D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018922:HL-60 Cells / Q000166:cytology*; D006801:Humans; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D012500:Santonin / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology*
C116441:2-methyl-1,25-dihydroxyvitamin D3; D016328:NF-kappa B; D012717:Sesquiterpenes; D014807:Vitamin D; D012500:Santonin; C002669:parthenolide