title: Cytotoxic versus anti-inflammatory effects in HeLa, Jurkat T and human peripheral blood cells caused by guaianolide-type sesquiterpene lactones.
abstract: Four guaianolide type sesquiterpene lactones (SL), namely the new 1,2-dihydro-3-oxo-costic acid guaianyl ester 3beta-O-(1,2-didehydro-3-oxo-costoyloxy)-4beta,10beta-dihydroxy-guaia-1(2)-en-6beta,12-olide (1) and 3beta-O-(1,2-didehydro-3-oxo-costoyloxy)-4beta,10beta-dihydroxy-guaia-1(2)-en-6alpha,12-olide (2), as well as the known moroccolide A [5alphaH-2beta,4-epoxy-3beta-hydroxy-guaia-1(10),11(13)-dien-6beta,12-olide, 3] and 3beta-O-(2-methylbutyryl)-moroccolide A [5alphaH-2beta,4-epoxy-3beta-(2-methylbutyryloxy)-guaia-1(10),11(13)-dien-6beta,12-olide, 4] were examined for their cytotoxic and anti-inflammatory effects in HeLa, Jurkat T and human peripheral blood mononuclear cells. Compounds 1, 2 and 4 were found to exert a strong cytotoxicity similar in potency in all investigated cell types, whereas 3 was significantly less active. Along with the cytotoxic effect compounds 1 and 4 showed a potent and comparable down-regulation of the mRNAs of the house-keeping genes beta-actin and GAP-DH in PBMCs after 20 h. In contrast, the down-regulation of the PMA-induced mRNA levels of the NF-kappaB-driven pro-inflammatory genes IL-2, IL-6, GM-CSF, TNF-alpha, and IL-1beta in PBMCs is significantly stronger with compound 4. Compound 3 did not significantly modulate cytokine mRNAs levels at biochemically relevant concentrations. The electromobility shift assay (EMSA), revealed a stronger inhibition of NF-kappaB for 1 (IC(50) 2.5 microM) than for 4 (IC(50) 5 microM). Both compounds were also subjected to an IL-6 luciferase reporter gene assay and showed IC(50) values of 1.0 (1) and 1.2 microM (4). Thus, the NF-kappaB inhibition measured by EMSA, as well as the IL-6 luciferase assay did not reflect the differential modulation of pro-inflammatory genes measured with RT-rt-PCR.
authors.affiliation: Department of Chemistry and Applied BioSciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Winterthurerstr. 190, CH-8057, Zürich, Switzerland.
authors.forename: Fatima
authors.initials: F
authors.lastname: Hilmi
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.forename: Paul
authors.initials: P
authors.lastname: Bremner
authors.forename: Silvia
authors.initials: S
authors.lastname: Valovic
authors.forename: Michael
authors.initials: M
authors.lastname: Heinrich
authors.forename: Otto
authors.initials: O
authors.lastname: Sticher
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D007783:Lactones / Q000494:pharmacology* / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D045789:Sesquiterpenes, Guaiane / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007783:Lactones; D012333:RNA, Messenger; D045789:Sesquiterpenes, Guaiane