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Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression.

ABSTRACT: Plants of the Asteraceae family have been used in traditional medicine for centuries due to their main antimicrobial and analgesic activities. A liniment from Artemisia californica has recently been tested on patients affected by either acute pain or chronic pain conditions with great success. The aim of this study was to evaluate the anti-inflammatory activity of sesquiterpene lactones (SLs), representing the majority in the Asteraceae family. Leucodin, ?-santonin and sclareolide (three SLs) were chosen to undergo chemical modifications. This pool of molecules underwent molecular modeling experiments using an in-house program, WATGEN, predicting the water network and its contribution to the overall affinity of the enzyme-ligand complex. The anti-inflammatory activity and the ability of compounds to modulate COX-2 expression have been evaluated in LPS-stimulated RAW 264.7 cells and in RIF-1 cells treated according to the Photodynamic Therapy (PDT) protocols using Photoprin (PH) as photosensitizer. Furthermore, commercially available assay kits were used to evaluate the concentration of PGE-2 and the direct inhibition of COX-2. All the tested molecules fit well in the enzyme binding pocket, but to get a substantial inhibition of the expression and activity of the enzyme as well as a reduction in the PGE2 concentration, high concentrations of the compounds are needed. The only exceptions being leucodin itself and FP6, one of the ?-santonin derivatives, presenting a CF3 functional group. We believe that this class of compounds has some interesting potential in the treatment of pain and inflammation. Although, the activity seems to be due to a mechanism related to the expression of the COX enzymes rather than on a direct inhibition.

SUBMITTER: Perri F

PROVIDER: S-EPMC6441754 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression.

Perri Filomena F Frattaruolo Luca L Haworth Ian I Brindisi Matteo M El-magboub Asma A Ferrario Angela A Gomer Charles C Aiello Francesca F Adams James David JD

Heliyon 20190327 3

Plants of the Asteraceae family have been used in traditional medicine for centuries due to their main antimicrobial and analgesic activities. A liniment from <i>Artemisia californica</i> has recently been tested on patients affected by either acute pain or chronic pain conditions with great success. The aim of this study was to evaluate the anti-inflammatory activity of sesquiterpene lactones (SLs), representing the majority in the Asteraceae family. Leucodin, α-santonin and sclareolide (three ...[more]

PMID: 30976671

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Project description:BACKGROUND:Interleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear. METHODS:We analyzed IL-33 gene expression in human colorectal cancer (CRC) tissues and carried out gene enrichment analysis with TCGA Data Portal. We studied CRC proliferation in vivo by inoculating MC38 tumors in IL-33 transgenic mice. We investigated the cell proliferation in vitro with primary CRC cells isolated from fresh human CRC tissues, human CRC cell line HT-29 and mouse CRC cell line MC38. To evaluate the proliferation modulating effects of recombinant IL-33 incubation and other administrated factors, we measured tumor growth, colony formation, cell viability, and the expression of Ki67 and proliferating cell nuclear antigen (PCNA). We used several inhibitors, prostaglandin E2 (PGE2) neutralizing antibody, ST2 blocking antibody and specific shRNA expressing plasmid to study the pathway mediating IL-33-induced CRC proliferation. The IL-33 receptor ST2 in human CRC tissues was detected by immunohistochemistry staining and western blotting. The ST2-positive or negative subsets of primary CRC cells were acquired by flow cytometry sorting. RESULTS:We found that IL-33 expression was correlated with the gene signature of cell proliferation in 394 human CRC samples. The MC38 tumors grew more rapidly and the tumor Ki67 and PCNA were expressed at higher levels in IL-33 transgenic mice than in wild-type mice. IL-33 promoted cell growth, colony formation and expression of Ki67 and PCNA in primary CRC cells as well as CRC cell lines. IL-33 activated cycloxygenase-2 (COX2) expression and increased PGE2 production, whereas the COX2 selective inhibitor and PGE2 neutralizing antibody abolished the proliferation promoting effect of IL-33. ST2 blockade, ST2-negative sorting, NF-?B specific inhibitor and NF-?B specific shRNA (shP65) abrogated the COX2 induction caused by IL-33. CONCLUSION:IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2. IL-33 functions via its receptor ST2 and upregulates COX2 expression through NF-?B signaling. Understanding the IL-33 signal transduction in CRC cells provides potential therapeutic targets for clinical treatment.

Dataset Information

Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression.

Publications

Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression.

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