mangostin and Brain-Neoplasms

Gliomas are a common type of primary brain tumor with glioblastoma multiforme accounting for the majority of human brain tumors. In this paper, high grade human malignant glioblastomas (MGs) including U87 MG and GBM 8401 were used to evaluate the antitumor effects of γ-mangostin, a xanthone derivative isolated and purified from the hull of the tropical fruit Garcinia mangostana. The γ-mangostin showed potent antiproliferative activity toward MGs in dose- and time-dependent manners. In addition, flow cytometric analysis of cell morphology in the apoptotic cells revealed an increase in hypodiploid cells in γ-mangostin treated U87 MG and GBM 8401 cells, while significant enhancement of intracellular peroxide production was detected in the same γ-mangostin treated cells by DCHDA assay and DiOC(6)(3) stain. g-Mangostin induced apoptosis, which in turn mediates cytotoxicity in human MG cells was prevented by the addition of catalase. Naturally derived medicines and herbal therapies are drawing increasing attention in regard to the treatment of many health issues, and this includes the testing of new phytochemicals or nutrients for brain tumor patients. This has led to γ-mangostin being identified as a potential leading compound for the development of an anti-brain tumor agent.

Topics: Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fruit; Garcinia mangostana; Glioma; Humans; Phytotherapy; Time Factors; Xanthones

In the course of our survey of natural compounds inhibiting prostaglandin E2 release and/or lipopolysaccharide (LPS)-induced transcriptional stimulation via NF-kappaB, a central regulator of inflammatory genes, from natural resources, we found garcinone B, a xanthone from callus tissue culture of Hypericum patulum, as a compound with such pharmacological activities, that is a derivative of gamma-mangostin which potently inhibits COX-1 and COX-2 activities to reduce PGE2 release from C6 rat glioma cells, and inhibits IKK activity to prevent NF-kappaB-dependent COX-2 gene transcription. Garcinone B, to a lesser extent, reduced A23187-induced increase in prostaglandin E2 release than gamma-mangostin and its structurally related compound, patulone, in C6 cells. This compound also prevented LPS-induced stimulation of NF-kappaB-dependent transcription. These results suggest that garcinone B becomes a unique pharmacological tool to investigate intracellular signaling pathways involved in inflammation.

Topics: Animals; Brain Neoplasms; Calcimycin; Cell Line, Tumor; Cyclooxygenase 1; Dinoprostone; Glioma; Hypericum; Inflammation Mediators; Lipopolysaccharides; NF-kappa B; Prostaglandin Antagonists; Rats; Transcription, Genetic; Xanthines; Xanthones

We investigated the effect of gamma-mangostin purified from the fruit hull of the medicinal plant Garcinia mangostana on spontaneous prostaglandin E(2) (PGE(2)) genase release and inducible cyclooxy-2 (COX-2) gene expression in C6 rat glioma cells. An 18-h treatment with gamma-mangostin potently inhibited spontaneous PGE(2) release in a concentration-dependent manner with the IC(50) value of approximately 2 microM, without affecting the cell viability even at 30 microM. By immunoblotting and reverse-transcription polymerase chain reaction, we showed that gamma-mangostin concentration-dependently inhibited lipopolysaccharide (LPS)-induced expression of COX-2 protein and its mRNA, but not those of constitutive COX-1 cyclooxygenase. Because LPS is known to stimulate inhibitor kappaB (IkappaB) kinase (IKK)-mediated phosphorylation of IkappaB followed by its degradation, which in turn induces nuclear factor (NF)-kappaB nuclear translocation leading to transcriptional activation of COX-2 gene, the effect of gamma-mangostin on the IKK/IkappaB cascade controlling the NF-kappaB activation was examined. An in vitro IKK assay using IKK protein immunoprecipitated from C6 cell extract showed that this compound inhibited IKK activity in a concentration-dependent manner, with the IC(50) value of approximately 10 microM. Consistently gamma-mangostin was also observed to decrease the LPS-induced IkappaB degradation and phosphorylation in a concentration-dependent manner, as assayed by immunoblotting. Furthermore, luciferase reporter assays showed that gamma-mangostin reduced the LPS-inducible activation of NF-kappaB-and human COX-2 gene promoter region-dependent transcription. gamma-Mangostin also inhibited rat carrageenan-induced paw edema. These results suggest that gamma-mangostin directly inhibits IKK activity and thereby prevents COX-2 gene transcription, an NF-kappaB target gene, probably to decrease the inflammatory agent-stimulated PGE(2) production in vivo, and is a new useful lead compound for anti-inflammatory drug development.

Topics: Animals; Brain Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Drug Interactions; Gene Expression; Glioma; I-kappa B Kinase; I-kappa B Proteins; Isoenzymes; Lipopolysaccharides; Male; Membrane Proteins; NF-kappa B; Pain; Prostaglandin-Endoperoxide Synthases; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; RNA, Messenger; Transcriptional Activation; Tumor Cells, Cultured; Xanthones