The effects of seven compounds 1-7, isolated from a tropical ascidian Lissoclinum cf. badium, on IL-8 production in PMA-stimulated HL-60 cells were examined. Lissoclibadins 2 (2) and 3 (3) and lissoclinotoxin F (5) increased the IL-8 production in a dose-dependent manner. Compounds 2 and 5 are structural isomers possessing dimeric structures of trans and cis-orientations, respectively, and showed a very similar activity on the induction of IL-8 levels. Compound 3 and lissoclinotoxin E (4) are also structural isomers having dimeric trans and cis-structures, respectively, but 4 did not induce the IL-8 production. Lissoclibadin 1 (1, trimeric compound) and two monomeric compounds (6 and 7) did not increase the IL-8 level. Therefore, the differences in their structures remarkably affected the IL-8 production activity, the inhibition of cell proliferation, and the survival of HL-60 cells. Lissoclibadin 2 was the most interesting compound of the seven metabolites tested in this study.

The in vitro growth inhibitory activity of lissoclibadins and lissoclinotoxins isolated from the tropical ascidian Lissoclinum cf. badium against nine human cancer cell lines was examined to evaluate their potential anticancer efficacy. Lissoclibadins 1 (1) and 2 (2), and lissoclinotoxin F (4) showed the strongest activity of the six compounds tested, which were more potent than the anticancer drug cisplatin. Compound 1 has a trimeric structure, and compounds 2 and 4 are structural isomers possessing dimeric structures connected by disulfide and sulfide bonds of trans- and cis-orientations, respectively. Lissoclibadin 3 (3), a dimeric compound connected by two sulfide bonds, and two monomeric compounds (5, 6) were less active than 1, 2, and 4. Lissoclibadin 2 (2) was the most interesting compound possessing potent inhibitory activity against colon (DLD-1 and HCT116), breast (MDA-MB-231), renal (ACHN), and non-small-cell lung (NCI-H460) cancer cell lines and showing no toxicity following a 50 mg/kg single treatment to mice, and preferable stability in rat plasma.

Verrucarin A is an inhibitor of protein synthesis. In this study, we examined the inhibitory action of verrucarin A on signal molecules. Verrucarin A partially inhibited the IL-8 production of a PMA-stimulated promyelocytic leukemia cell line (HL-60 cells), and the effect was related to the inhibition of NF-κB activation at noncytotoxic concentrations. Moreover, the inhibition of mitogen activated protein (MAP) kinase by verrucarin A was especially strong with p38- and JNK-phosphorylation. The findings show a new action of verrucarin A, and it is expected that this action relaxes the signal activation in response to stress.

Eight sesquiterpene quinones: ilimaquinone (1), smenospongidine (3),smenospongiarine (5), smenospongine (7), and their corresponding 5-epimers 2, 4, 6, and 8,isolated from the Palauan marine sponge Hippospongia sp., were examined regarding theireffects on TNF-α production in LPS-stimulated RAW 264.7 cells. 5-Epi-smenospongine(8) promoted the production of TNF-α to a level three times greater than the control at10 μM, but compounds 1-7 did not show apparent activity. The results suggest that thecis-decaline ring and a primary amine in the benzoquinone ring are necessary for activity.This is the first study to report the modulation of TNF-α production by a sesquiterpenequinone.

Alprazolam is a hypnotic/tranquilizer that has been shown to specifically inhibit the platelet-activating factor (PAF)-induced aggregation of human platelets. The goal of this study was to elucidate whether alprazolam modulates IL-1α-initiated responses. For this purpose we investigated the effects of alprazolam on the IL-1α-induced production of inflammatory cytokines (IL-8 and monocyte chemoattractant protein 1 (MCP-1)) in a human glioblastoma cell line, T98G, and explored the signaling pathways involved. We found that alprazolam inhibited IL-1α-elicited MCP-1 production within a range of 0.1–3 μM. In contrast, it did not inhibit IL-1α-induced IL-8 production. Although NF-κB is involved in regulating the IL-1α-induced expression of MCP-1 and IL-8, the degradation of IκB-α stimulated by IL-1α was not inhibited by alprazolam. Alprazolam prevented NF-κB from binding to the MCP-1 promoter region (the A2 and A1 oligonucleotide probes), but binding of NF-κB to IL-8/NF-κB was not inhibited. Moreover, alprazolam inhibited c-Rel/p50 binding to the A2 oligonucleotide probe, but not p50/p65 from binding to the IL-8/NF-κB site. While AP-1 is involved in regulating the IL-1α-induced expression of IL-8, but not MCP-1, alprazolam potentiated the binding of c-Jun/c-Fos to the AP-1 oligonucleotide probe. These results show that the inhibition of IL-1α-mediated MCP-1 production by alprazolam is mainly due to inhibition of c-Rel/p65 and c-Rel/p50 binding to the MCP-1 promoter region, since alprazolam did not affect the IL-1α-mediated activation of NF-κB (p50/p65) or AP-1 (c-Jun/c-Fos) binding to the IL-8 promoter region. In conclusion, a new action of alprazolam was elucidated, as shown in the inhibition of c-Rel/p65- and c-Rel/p50-regulated transcription.