santonin and parthenolide

Here we report the prevention and reversal of cocaine-induced behaviors in planarian worms by parthenolide and two related cyclic sesquiterpene lactones (SL), costunolide and santonin. Using established protocols, we studied two cocaine-induced behavioral effects in planaria; the induction of motility decrease and the induction of C-like hyperkinesia. Cocaine, parthenolide, costunolide, santonin, and a lactone-less cyclic sesquiterpene, beta-eudesmol, decreased planarian motility in a concentration-dependent manner. Only cocaine induced C-like hyperkinesia. At concentrations that did not show any motility decrease, parthenolide, costunolide and santonin, but not beta-eudesmol, significantly reduced the cocaine-induced motility decrease and C-like hyperkinesia, in a concentration-dependent manner. Furthermore, parthenolide, costunolide and santonin were able to rescue planaria from C-like hyperkinesia, after the worms were exposed to cocaine. Conversely, cocaine at a concentration that did not show any measurable effects (10 microM), was able to alleviate the SL-, but not the beta-eudesmol-induced motility decrease. Liquid Chromatography/Mass Spectrometry experiments demonstrated that cocaine does not interact directly with any of the cyclic sesquiterpenoids, which suggests specific biochemical targets for these compounds in planarians. Our data suggests a common binding site for cocaine and the sesquiterpene lactones in planarians.

Topics: Algorithms; Animals; Behavior, Animal; Chromatography, High Pressure Liquid; Cocaine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Hyperkinesis; Mass Spectrometry; Motor Activity; Planarians; Santonin; Sesquiterpenes; Sesquiterpenes, Eudesmane; Spectrometry, Mass, Electrospray Ionization

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.

Topics: Cell Differentiation; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; HL-60 Cells; Humans; Monocytes; NF-kappa B; Santonin; Sesquiterpenes; Time Factors; Vitamin D