Cytotoxic versus anti-inflammatory effects in HeLa, Jurkat T and human peripheral blood cells caused by guaianolide-Type sesquiterpene lactones

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 [5alpha H-2beta ,4-epoxy-3beta -hydroxy-guaia-1(10),11(13)-dien-6beta ,12-olide, 3] and 3beta -O-(2-methylbutyryl)-moroccolide A [5alpha H-2beta ,4-epoxy-3beta -(2-methylbutyryloxy)-guaia-1(10),11(13)-dien-6beta ,12-olide, 4] were examd. for their cytotoxic and anti-inflammatory effects in HeLa, Jurkat T and human peripheral blood mononuclear cells. Compds. 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 compds. 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-kB-driven pro-inflammatory genes IL-2, IL-6, GM-CSF, TNF-alpha , and IL-1beta in PBMCs is significantly stronger with compd. 4. Compd. 3 did not significantly modulate cytokine mRNAs levels at biochem. relevant concns. The electromobility shift assay (EMSA), revealed a stronger inhibition of NF-kB for 1 (IC50 2.5 micro M) than for 4 (IC50 5 micro M). Both compds. were also subjected to an IL-6 luciferase reporter gene assay and showed IC50 values of 1.0 (1) and 1.2 micro M (4). Thus, the NF-kB 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