Sesquiterpene lactones from Lychnophora species: Antinociceptive, anti-inflammatory, and antioxidant pathways to treat acute gout.

ETHNOPHARMACOLOGICAL RELEVANCE: Lychnophora trichocarpha and Lychnophora passerina are species used in folk medicine to treat inflammation, pain, and rheumatism. Previous studies have demonstrated the anti-inflammatory effect of ethanol extracts of these species and identified that sesquiterpene lactones contribute to this activity. AIM OF THE STUDY: Gout is an acute inflammatory arthritis caused by the deposition of monosodium urate (MSU) crystals in joints. Inflammation in joints induces oxidative stress in defense cells, releasing pro-inflammatory mediators. This study has three objectives: (1) to demonstrate the effects of sesquiterpene lactones lychnopholide and eremantholide C isolated from L. trichocarpha and goyazensolide isolated from L. passerina on arthritis induced by MSU crystals in C57BL6 mice; (2) to determine whether or not these compounds can inhibit the migration of neutrophils and the release of TNF-α and IL-1ß cytokines in the inflammation region; and (3) to evaluate the effects of sesquiterpene lactones on the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the cartilage of C57BL/6 mice with gouty arthritis. MATERIALS AND METHODS: The anti-inflammatory, antinociceptive, and antioxidant activities of sesquiterpene lactones in C57BL/6 mice with MSU crystal-induced arthritis were evaluated. In our experimental model, the mice were injected with MSU crystals in the tibiofemoral joint to induce arthritis and then treated with indomethacin, vitamin C, and sesquiterpene lactones. Nociception was evaluated before and after inflammation induction and treatments, neutrophil migration, IL-1ß and TNF-α concentrations, and SOD and CAT activities. RESULTS: Sesquiterpene lactones exerted an anti-inflammatory effect by inhibiting neutrophil migration and TNF-α production. These compounds also demonstrated antinociceptive and antioxidant activities. CONCLUSION: Lychnopholide, eremantholide C, and goyazensolide improved the inflammation induced by MSU crystals by inhibiting the migration of neutrophils to the inflamed area and by blocking the release of the pro-inflammatory cytokine TNF-α. In addition, sesquiterpene lactones reduced oxidative stress by activating SOD and CAT. These results suggest that sesquiterpene lactones have anti-gout activity through the inflammation, pain, and oxidative stress pathways.

Activity of the sesquiterpene lactone goyazensolide against Trypanosoma cruzi in vitro and in vivo.

BACKGROUND: The current drugs for Chagas disease treatment present several limitations. METHODS: The sesquiterpene lactone goyazensolide (GZL) was evaluated regarding to cytotoxicity and trypanocidal activity against amastigotes, selectivity index (SI) in vitro, acute toxicity and anti-Trypanosoma cruzi activity in vivo. RESULTS: The in vitro cytotoxicity in H9c2 cells was observed at doses >250 ng mL-1 of GZL and the SI were of 52.82 and 4.85 (24 h) and of 915.00 and 41.00 (48 h) for GZL and BZ, respectively. Nephrotoxicity and hepatotoxicity were not verified. Treatment with GZL of mice infected with CL strain led to a significant decrease of parasitaemia and total survival at doses of 1 and 3 mg kg-1 day-1 by oral and IV, respectively. This last group cured 12.5% of the animals (negativation of HC, PCR, qPCR and ELISA). Animals infected with Y strain showed significant decrease of parasitaemia and higher negativation in all parasitological tests in comparison to BZ and control groups, but were ELISA reactive, as well as the BZ group, but mice treated with 5.0 mg kg-1 day-1 by oral were negative in parasitological tests and survived. CONCLUSION: GZL was more active against T. cruzi than benznidazole in vitro and presented important therapeutic activity in vivo in both T. cruzi strains.

Chemistry and biology of ophiobolin A and its congeners.

Ophiobolin A is a fungal secondary metabolite that was found to have significant activity against apoptosis-resistant glioblastoma cells through the induction of a non-apoptotic cell death, offering an innovative strategy to combat this aggressive cancer. The current article aims to make the bridge between the anti-cancer effects of ophiobolin A and its unique reaction with primary amines and suggests that pyrrolylation of lysine residues on its intracellular target protein(s) and/or phosphatidylethanolamine lipid is responsible for its biological effects. The article also discusses chemical derivatization of ophiobolin A to establish first synthetically generated structure-activity relationship. Finally, the reported total synthesis efforts toward the ophiobolin class of sesterterpenes are discussed and identified as a fertile area for improvement in pursuit of these molecules as anticancer agents.

Grifolic acid causes osteosarcoma cell death in vitro and in tumor-bearing mice.

Grifolic acid is a natural compound isolated from the fungus Albatrellus confluens. In the present study, we assessed the effects of grifolic acid on human osteosarcoma cells. We found that grifolic acid dose- and time-dependently induced cell death in the U-2 OS, MG-63, Saos-2, and 143B human osteosarcoma cell lines. Grifolic acid decreased osteosarcoma cell mitochondrial membrane potential, ATP production, and cellular NADH levels, but did not impact mitochondrial membrane potential in isolated mitochondria from human osteosarcoma cells. Intratumoral injection of grifolic acid also promoted tumor cell death and prolonged survival in nude mice bearing human osteosarcoma xenografts. Grifolic acid had no obvious toxicity in mice, with no histological changes in liver, kidney, lung, or heart, and no changes in blood cell counts or levels of plasma total protein, alanine aminotransferase, or aspartate aminotransferase. These results show that grifolic acid induces osteosarcoma cell death by inhibiting NADH generation and ATP production without obvious toxicity. Intratumoral injection of grifolic acid may be a promising anti-osteosarcoma therapeutic option in patients.

The Biological Activities of Sesterterpenoid-Type Ophiobolins.

Ophiobolins (Ophs) are a group of tricarbocyclic sesterterpenoids whose structures contain a tricyclic 5-8-5 carbotricyclic skeleton. Thus far, 49 natural Ophs have been reported and assigned into A-W subgroups in order of discovery. While these sesterterpenoids were first characterized as highly effective phytotoxins, later investigations demonstrated that they display a broad spectrum of biological and pharmacological characteristics such as phytotoxic, antimicrobial, nematocidal, cytotoxic, anti-influenza and inflammation-promoting activities. These bioactive molecules are promising drug candidates due to the developments of their anti-proliferative activities against a vast number of cancer cell lines, multidrug resistance (MDR) cells and cancer stem cells (CSCs). Despite numerous studies on the biological functions of Ophs, their pharmacological mechanism still requires further research. This review summarizes the chemical structures, sources, and biological activities of the oph family and discusses its mechanisms and structure-activity relationship to lay the foundation for the future developments and applications of these promising molecules.

Ophiobolin A, a sesterpenoid fungal phytotoxin, displays different mechanisms of cell death in mammalian cells depending upon the cancer cell origin.

Herein we have undertaken a systematic analysis of the effects of the fungal derivative ophiobolin A (OphA) on eight cancer cell lines from different tissue types. The LD50 for each cell line was determined and the change in cell size determined. Flow cytometric analysis and western blotting were used to assess the cell death markers for early apoptosis, late apoptosis and necrosis, and the involvement of the caspase signalling pathway. Alterations in calcium levels and reactive oxygen species were assessed due to their integral involvement in intracellular signalling. Subsequently, the endoplasmic reticulum (ER) and mitochondrial responses were investigated more closely. The extent of ER swelling, and the upregulation of proteins involved in the unfolded protein responses (UPR) were seen to vary according to cell line. The mitochondria were also shown to behave differently in response to the OphA in the different cell lines in terms of the change in membrane potential, the total area of mitochondria in the cell and the number of mitochondrial bifurcations. The data obtained in the present study indicate that the cancer cell lines tested are unable to successfully activate the ER stress/UPR responses, and that the mitochondria appear to be a central player in OphA-induced cancer cell death.

Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90.

Two new scalarane sesterterpenoids, 12ß-(3'ß-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12ß-(3'ß-hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (2), along with one known tetraprenyltoluquinol-related metabolite (3), were isolated from the sponge Carteriospongia sp. In leukemia Molt 4 cells, 1 at 0.0625 µg/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase IIα expression. The apoptotic-inducing effect of 3 was supported by the in vivo experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound 1 apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis, 1 exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70S6k, NFκB, Raf-1, p-GSK3ß, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF 1 and HSF1 were suppressed by the use of 1. However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after 1 treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.

Furospinosulin-1, Marine Spongean Furanosesterterpene, Suppresses the Growth of Hypoxia-Adapted Cancer Cells by Binding to Transcriptional Regulators p54(nrb) and LEDGF/p75.

Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. Cancer research has therefore focused on the identification of molecules responsible for hypoxia adaptation in cancer cells, as well as the development of new compounds with action against hypoxia-adapted cancer cells. The marine natural product furospinosulin-1 (1) has displayed hypoxia-selective growth inhibition against cultured cancer cells, and has shown in vivo anti-tumor activity, although its precise mode of action and molecular targets remain unclear. In this study, we found that 1 is selectively effective against hypoxic regions of tumors, and that it directly binds to the transcriptional regulators p54(nrb) and LEDGF/p75, which have not been previously identified as mediators of hypoxia adaptation in cancer cells.

Sesquiterpene dimer (DSF-52) from Artemisia argyi inhibits microglia-mediated neuroinflammation via suppression of NF-κB, JNK/p38 MAPKs and Jak2/Stat3 signaling pathways.

Microglia-involved neuroinflammation is thought to promote brain damage in various neurodegenerative disorders. Therefore, novel therapeutics suppressing microglia over-activation could prove useful for neuroprotection in inflammation-mediated neurodegenerative diseases. DSF-52 is a novel sesquiterpene dimer compound isolated from medical plant Artemisia argyi by our group. In this study, we investigated whether DSF-52 inhibited the neuroinflammatory responses in lipopolysaccharide (LPS)-activated microglia. Our findings showed that DSF-52 inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), as well as mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin-1ß (IL-1ß), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage inflammatory protein-1α (MIP-1α) in LPS-activated BV-2 microglia. Moreover, DSF-52 markedly up-regulated mRNA levels of anti-inflammatory cytokine IL-10. Mechanism study indicated that DSF-52 suppressed Akt/IκB/NF-κB inflammation pathway against LPS treatment. Also, DSF-52 down-regulated the phosphorylation levels of JNK and p38 MAPKs, but not ERK. Furthermore, DSF-52 blocked Jak2/Stat3 dependent inflammation pathway through inhibiting Jak2 and Stat3 phosphorylation, as well as Stat3 nuclear translocation. We concluded that the inhibitory ability of DSF-52 on microglia-mediated neuroinflammation may offer a novel neuroprotective modality and could be potentially useful in inflammation-mediated neurodegenerative diseases.

Hypoxia-selective growth inhibition of cancer cells by furospinosulin-1, a furanosesterterpene isolated from an Indonesian marine sponge.

It is generally accepted that cancer cells, which have adapted to the hypoxic environments in tumor tissues, aggravate cancer pathology by promoting tumor growth, angiogenesis, metastasis, and drug resistance. Therefore, compounds that selectively inhibit the growth of tumor cells in hypoxic environments are expected to provide new leads for promising anticancer drugs. Furospinosulin-1, a marine-sponge-derived furanosesterterpene, exhibited selective antiproliferative activity against DU145 human prostate cancer cells under hypoxic conditions in concentrations ranging from 1 to 100 µM. Furospinosulin-1 also demonstrated antitumor activity at 10-50 mg kg(-1) oral administration in a mouse model inoculated with sarcoma S180 cells. Mechanistic analysis revealed that furospinosulin-1 suppresses transcription of the insulin-like growth factor-2 gene (IGF-2), which is selectively induced under hypoxic conditions through prevention of the binding of nuclear proteins to the Sp1 consensus sequence in the IGF-2 promoter region.