mangostin and Neoplasms

α-Mangostin (α-MG) is a natural xanthone obtained from the pericarps of mangosteen. It exhibits excellent potential, including anti-cancer, neuroprotective, antimicrobial, antioxidant, and anti-inflammatory properties, and induces apoptosis. α-MG controls cell proliferation by modulating signaling molecules, thus implicated in cancer therapy. It possesses incredible pharmacological features and modulates crucial cellular and molecular factors. Due to its lesser water solubility and pitiable target selectivity, α-MG has limited clinical application. As a known antioxidant, α-MG has gained significant attention from the scientific community, increasing interest in extensive technical and biomedical applications. Nanoparticle-based drug delivery systems were designed to improve the pharmacological features and efficiency of α-MG. This review is focused on recent developments on the therapeutic potential of α-MG in managing cancer and neurological diseases, with a special focus on its mechanism of action. In addition, we highlighted biochemical and pharmacological features, metabolism, functions, anti-inflammatory, antioxidant effects and pre-clinical applications of α-MG.

Topics: Antioxidants; Apoptosis; Humans; Neoplasms; Solubility; Xanthones

Stimulator of interferon genes (STING) is an adaptor protein that induces the secretion of type I interferons and proinflammatory cytokines and is triggered by cytosolic DNA of pathogen and host origins. Given that STING is a mediator in the immune system, pharmacological modulation of STING has shown viable therapeutic effects for pathogen infection, cancer, and inflammatory diseases. In the past decade, the substantial development in this field has encouraged the discovery of STING modulators. Here, we will summarize the current understanding of STING structure, survey the status quo of STING modulators, compare established bioassay methods, review the chemical structures and bioactivities of agonists and inhibitors, and propose suggestions and insights for the future exploitation of STING modulators.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Autoimmune Diseases; Binding Sites; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Membrane Proteins; Neoplasms; Protein Structure, Secondary; Signal Transduction

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

The high rate of incidence and mortality caused by breast cancer encourage urgent research to immediately develop new diagnostic and therapeutic agents for breast cancer. Alpha mangostin (AM) is a natural compound reported to have anti-breast cancer properties. Its electron-donating groups structure allows it to be labeled with an iodine-131 radioisotope to develop a candidate of a diagnostic and therapeutic agent for breast cancer. This study aims to prepare the [

Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; Iodine; Iodine Radioisotopes; Neoplasms; Tissue Distribution; Vero Cells

Alpha-mangostin, a natural xanthone mainly extracted from the pericarp of

Topics: Drug Delivery Systems; Humans; Lipids; Nanoparticles; Neoplasms; Polymers; Transferrin; Xanthones

Alpha-mangostin (α-mangostin) has been identified as a naturally occurring compound with potential anticancer properties. It can induce apoptosis and inhibit the growth and metastasis of cancer cells. Moreover, α-mangostin reduces the mechanical stiffness of lung cancer cells. The objective of this study was to determine the effect of α-mangostin on the mechanical stiffness of various cells, as well as cell viability. The following cell types were examined: human fibroblast TIG-1 cells, human cancerous HeLa cells, human embryonic kidney HEK293 cells, mouse macrophage RAW 264.7 cells, and human myeloblasts KG-1 cells. Cells were treated with α-mangostin, and then examined for cell viability, actin cytoskeletal structures, and surface mechanical stiffness using atomic force microscopy. α-Mangostin demonstrated cytotoxicity against TIG-1, HeLa, HEK293, and KG-1 cells, but not against RAW 264.7 cells. The cytotoxic effect of α-mangostin varies according to cell type. On the other hand, α-mangostin reduced the mechanical stiffness of all cell types, including RAW 264.7 cells. Upon treatment with α-mangostin, F-actin was slightly reduced but the actin cytoskeletal structures were little altered in these cells. Thus, reducing mechanical stiffness of animal cells is an inherent effect of α-mangostin. Our results show that α-mangostin is a naturally occurring compound with potential to change the actin cytoskeletal micro-structures and reduce the surface stiffness of various cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biomechanical Phenomena; HeLa Cells; Humans; Mice; Neoplasms; RAW 264.7 Cells; Xanthones

We purified and identified eight xanthones from mangosteen (Garcinia mangostana L.) and investigated whether these compounds inhibited the activities of mammalian DNA polymerases (Pols) and human DNA topoisomerases (Topos). β-Mangostin was the strongest inhibitor of both mammalian Pols and human Topos among the isolated xanthones, with 50% inhibitory concentration (IC50) values of 6.4-39.6 and 8.5-10 µM, respectively. Thermal transition analysis indicated that β-mangostin did not directly bind to double-stranded DNA, suggesting that this compound directly bound the enzyme protein rather than the DNA substrate. β-Mangostin showed the strongest suppression of human cervical cancer HeLa cell proliferation among the eight compounds tested, with a 50% lethal dose (LD50) of 27.2 µM. This compound halted cell cycle in S phase at 12-h treatment and induced apoptosis. These results suggest that decreased proliferation by β-mangostin may be a result of the inhibition of cellular Pols rather than Topos, and β-mangostin might be an anticancer chemotherapeutic agent.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cattle; Cell Cycle; Cell Proliferation; DNA; DNA-Directed DNA Polymerase; DNA, Single-Stranded; Garcinia mangostana; HeLa Cells; Humans; Indoles; Inhibitory Concentration 50; Neoplasms; Nucleic Acid Synthesis Inhibitors; Rats; Topoisomerase Inhibitors; Xanthones

A xanthone-derived natural product, α-mangostin is isolated from various parts of the mangosteen, Garcinia mangostana L. (Clusiaceae), a well-known tropical fruit. Novel xanthone derivatives based on α-mangostin were synthesized and evaluated as anti-cancer agents by cytotoxicity activity screening using 5 human cancer cell lines. Some of these analogs had potent to moderate inhibitory activities. The structure-activity relationship studies revealed that phenol groups on C3 and C6 are critical to anti-proliferative activity and C4 modification is capable to improve both anti-cancer activity and drug-like properties. Our findings provide new possibilities for further explorations to improve potency.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Garcinia mangostana; Humans; Neoplasms; Structure-Activity Relationship; Xanthones

We found that the ethanol extract of mangosteen (Garcinia mangostana L.) fruit rind had a strong inhibitory effect on mammalian DNA polymerase (pol) activity and isolated α-mangostin as a potent pol inhibitor from the extract. In this study, the inhibitory activities against mammalian pols by α-mangostin and its related five compounds, 3-isomangostin, xanthone, 9,10-anthraquinone, 9-anthracenecarboxylic acid, and anthracene, were investigated. α-Mangostin was the most potent inhibitor of the mammalian pol species among the tested compounds, with IC₅₀ values of 14.8-25.6 μM. This compound also inhibited human DNA topoisomerases (topos) I and II activities with IC₅₀ values of 15.0 and 7.5 μM, respectively, but did not inhibit the activities of other DNA metabolic enzymes tested. α-Mangostin also did not directly bind to double-stranded DNA as determined by thermal transition analysis. α-Mangostin was found to suppress human colon HCT116 carcinoma cell proliferation with an LC₅₀ of 18.5 μM, inhibit the activity of cellular topos, halt cell cycle in the G2/M phase, and induce apoptosis. These results suggest that decreased proliferation by α-mangostin may be a result of the inhibition of cellular topos rather than pols, and α-mangostin might be an anticancer chemotherapeutic agent.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cattle; Cell Line, Tumor; Cell Proliferation; DNA-Directed DNA Polymerase; Enzyme Inhibitors; Escherichia coli Proteins; G2 Phase; Humans; Isoenzymes; Mice; Neoplasm Proteins; Neoplasms; Nucleic Acid Synthesis Inhibitors; Plant Proteins; Rats; Recombinant Proteins; Topoisomerase Inhibitors; Xanthones

The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound α-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of α-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers.. Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with α-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by α-mangostin, in vitro studies were also conducted.. Not only were in vivo survival rates significantly higher in the 20 mg/kg/day α-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues. In vitro, α-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by α-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that α-mangostin significantly decreased the levels of phospho-Akt-threonine 308 (Thr308), but not serine 473 (Ser473), in both mammary carcinoma cell cultures and mammary carcinoma tissues in vivo.. Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of α-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, α-mangostin may have chemopreventive benefits and/or prove useful as an adjuvant therapy, or as a complementary alternative medicine in the treatment of breast cancer.

Topics: Animals; Antineoplastic Agents; Female; Garcinia mangostana; Humans; Lymph Nodes; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mutation; Neoplasm Metastasis; Neoplasms; Transplantation, Heterologous; Treatment Outcome; Tumor Suppressor Protein p53; Xanthones