• IMMUNE NETWORK
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• 제12권6호
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• pp.253-260
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• 2012

${\alpha}$-Mangostin is a xanthon derivative contained in the fruit hull of mangosteen (Garcinia mangostana L.), and the administration of ${\alpha}$-Mangostin inhibited the growth of transplanted colon cancer, Her/CT26 cells which expressed Her-2/neu as tumor antigen. Although ${\alpha}$-Mangostin was reported to have inhibitory activity against sarco/endoplasmic reticulum $Ca^{2+}$ ATPase like thapsigargin, it showed different activity for autophagy regulation. In the current study, we found that ${\alpha}$-Mangostin induced autophagy activation in mouse intestinal epithelial cells, as GFP-LC3 transgenic mice were orally administered with 20 mg/kg of ${\alpha}$-Mangostin daily for three days. However, the activation of autophagy by ${\alpha}$-Mangostin did not significantly increase OVA-specific T cell proliferation. As we assessed ER stress by using XBP-1 reporter system and phosphorylation of $eIF2{\alpha}$, thapsigargin-induced ER stress was significantly reduced by ${\alpha}$-Mangostin. However, coadministration of thapsigargin with ${\alpha}$-Mangostin completely blocked the antitumor activity of ${\alpha}$-Mangostin, suggesting ER stress with autophagy blockade accelerated tumor growth in mouse colon cancer model. Thus the antitumor activity of ${\alpha}$-Mangostin can be ascribable to the autophagy activation rather than ER stress induction.

• Biomolecules & Therapeutics
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• 제24권6호
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• pp.604-609
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• 2016

5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5-fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5-FU bears a significant importance. In the present study, we have found that ${\alpha}$-mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of ${\alpha}$-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4-HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that ${\alpha}$-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated ${\alpha}$-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that ${\alpha}$-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5-FU by activating apoptosis pathway.

• Toxicological Research
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• 제35권2호
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• pp.167-179
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• 2019

Ovarian cancer is the fifth main cause of pre-senescent death in women. Although chemotherapy is generally an efficient treatment, its side effects and the occurrence of chemotherapeutic resistance have prompted the need for alternative treatments. In this study, ${\alpha}$-mangostin and apigenin were evaluated as possible anticancer alternatives to the chemotherapeutic drug doxorubicin, used herein as a positive control. The ovarian adenocarcinoma cell line SKOV-3 (ATCC No. HTB77) was used as model ovarian cancer cells, whereas the skin fibroblast line CCD-986Sk (ATCC No. CRL-1947) and lung fibroblast line WI-38 (ATCC No. CCL-75) were used as model untransformed cells. Apigenin and doxorubicin inhibited the growth of SKOV-3 cells in a dose- and time-dependent manner. After 72 hr exposure, doxorubicin was mostly toxic to SKOV-3 cells, whereas apigenin was toxic to SKOV-3 cells but not CCD-986Sk and WI-38 cells. ${\alpha}$-Mangostin was more toxic to SKOV-3 cells than to CCD-986Sk cells. A lower cell density, cell shrinkage, and more unattached (floating round) cells were observed in all treated SKOV-3 cells, but the greatest effects were observed with ${\alpha}$-mangostin. With regard to programmed cell death, apigenin caused early apoptosis within 24 hr, whereas ${\alpha}$-mangostin and doxorubicin caused late apoptosis and necrosis after 72 hr of exposure. Caspase-3 activity was significantly increased in ${\alpha}$-mangostin-treated SKOV-3 cells after 12 hr of exposure, whereas only caspase-9 activity was significantly increased in apigenin-treated SKOV-3 cells at 24 hr. Both ${\alpha}$-mangostin and apigenin arrested the cell cycle at the $G_2/M$ phase, but after 24 and 48 hr, respectively. Significant upregulation of BCL2 (apoptosis-associated gene) and COX2 (inflammation-associated gene) transcripts was observed in apigenin- and ${\alpha}$-mangostin-treated SKOV-3 cells, respectively. ${\alpha}$-Mangostin and apigenin are therefore alternative options for SKOV-3 cell inhibition, with apigenin causing rapid early apoptosis related to the intrinsic apoptotic pathway, and ${\alpha}$-mangostin likely being involved with inflammation.

• Natural Product Sciences
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• 제22권3호
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• pp.147-153
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• 2016

Inflammation plays an important role in host defense against external stimuli such as infection by pathogen, endotoxin or chemical exposure by the production of the inflammatory mediators that produced by macrophage. Anti-inflammatory factor is important to treat the dangers of chronic inflammation associated with chronic disease. This research aims to analyze the anti-inflammatory effects of Garcinia mangostana L. peel extract (GMPE), ${\alpha}$-mangostin, and ${\gamma}$-mangostin in LPS-induced murine macrophage cell line (RAW 264.7) by inhibiting the production of inflammatory mediators. The cytotoxic assay of G. mangostana L. extract, ${\alpha}$-mangostin, and ${\gamma}$-mangostin were performed by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) to determine the safe and non-toxic concentration in RAW 264.7 for the further assay. The concentration of inflammatory mediators (COX-2, IL-6, and IL-$1{\beta}$) were measured by the ELISA-based assay and NO by the nitrate/nitrite colorimetric assay in treated LPS-induced RAW 264.7 cells. The inhibitory activity was determined by the reducing concentration of inflammatory mediators in treated LPS-induced RAW 264.7 over the untreated cells. This research revealed that GMPE, ${\alpha}$-mangostin, and ${\gamma}$-mangostin possess the anti-inflammatory effect by reducing COX-2, IL-6, IL-$1{\beta}$, and NO production in LPS-induces RAW 264.7 cells.

• Advances in materials Research
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• 제9권4호
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• pp.251-263
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• 2020

α-mangostin imprinted polymers have been synthesized by a non-covalent imprinting approach with α-mangostin as a template molecule. The α-mangostin molecularly imprinted polymers (MIPs) prepared by radical polymerization using methacrylic acid, ethlylene glycol dimethacrylate, benzoyl peroxide, and acetonitrile, as a monomer, crosslinker, initiator, and porogen, respectively. The template was removed by using methanol:acetic acid 90:10 (v/v). The physical characteristics of the polymers were investigated by Fourier Transform Infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The rebinding studies were carried out by batch methods. The results exhibited that the MIPs was able to adsorb the α-mangostin at pH 2 and the contact time of 180 min. The kinetic adsorption data of α-mangostin performed the pseudo-second order model and followed the Langmuir isotherm model with the adsorption capacity of 16.19 mg·g-1. MIPs applied as a sorbent material in solid-phase extraction, namely molecularly imprinted solid-phase extraction (MISPE) and it shows the ability for enrichment and clean-up of α-mangostin from the complex matrix in medicinal herbal product and crude extract of mangosteen (Garcinia mangostana L.) pericarp. Both samples, respectively, which were spiked with α-mangostin gives recovery more than 90% after through by MISPE in all concentration ranges.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1998년도 Proceedings of UNESCO-internetwork Cooperative Regional Seminar and Workshop on Bioassay Guided Isolation of Bioactive Substances from Natural Products and Microbial Products
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• pp.170-170
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• 1998

In order to discover new types of 5-hydroxytryptamine antagonists, we have devoted our attention to investigating naturally occurring compounds having anti-5HT activity in vitro. Recently, ${\gamma}$-mangostin [1,3,6,7-tetrahydroxy-2,8-bis(3-methyl-2-bytenyl)-9H-xanthen-9-one] from the fruit hull of Garcinia mangostana Linn has been shown to be a selective antagonist for 5-hydroxytryptamine$_{2A}$ receptors in smooth muscle and platelets. It is of interesting that y-mangostin which does not have a nitrogen atom, possesses marked 5-$HT_{2A}$ receptor blocking activity. The present study was undertaken to investigate the effects of ${\gamma}$-mangostin on central 5-HT receptors by using animal behavioural models. Intracerebronventricular injection of ${\gamma}$-mangostin (10-40n mol/mouse) inhibited 5-fluoro-${\alpha}$-methyltryptamin (5-FMT) (45 mg kg$^{-1}$, i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (5-HT-uptake inhibitor). Neither the 5-FMT- nor the 8-hydroxy-2-( di-n-propylamino )tetralin (5-HT$_{1A}$-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by ${\gamma}$-mangostin. The locomotor activity stimulated by 5-FMT through the activation of at-adrenoceptors did not alter in the presence of ${\gamma}$-mangostin. 5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. ${\gamma}$-Mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation and the binding of [$^3H$]-spiperone, a specific 5-$HT_{2A}$ receptor antagonist, to mouse brain membranes. Kinetic analysis of the [$^H3$]-spiperone binding revealed that ${\gamma}$-mangostin increased the $_{d}$ value without affecting the $B_{max}$ value, indicating the mode of the competitive nature of the inhibition by ${\gamma}$-mangostin. These results suggest that ${\gamma}$-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-$HT_{2A}$ receptors not by blocking the release of 5-HT from the central neurone. ${\gamma}$-Mangostin is a promising 5-$HT_{2A}$ receptors antagonist in the central nervous system.m.

• Natural Product Sciences
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• 제12권3호
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• pp.138-143
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• 2006

Our continuing interest on Garcinia and Mesua species has led us to carry out a detail study on the chemistry of the root bark of Garcinia mangostana (Guttiferae) since this part of the plant has not been investigated before, and the strm bark of Mesua corneri (Guttiferae) an uninvestigated species. This study has yielded six xanthones, ${\alpha}-mangostin$ (1), ${\beta}-mangostin$ (2), ${\gamma}-mangostin$ (3), garcinone-D (4), mangostanol (5) and gartanin (6) from Garcinia mangostana and two xanthones rubraxanthone (7) and inophyllin B (8) from Mesua corneri. Structural elucidations were achieved using $^1H,\;^{13}C$ NMR and MS data. The crude hexane and chloroform extracts of the root bark of Garcinia mangostana and the hexane extract of the stem bark of Mesua corneri were found to be active against CEM-SS cell lines with $IC_{50}$ values less than $30\;{mu}g/ml$. Moreover, ${\gamma}-mangostin$ gave a very low $LC_{50}$ value of $4.7\;{mu}g/ml$ while rubraxanthone gave an $LC_{50}$ value of $5.0\;{mu}g/ml$ indicating these two compounds to be potential lead compounds for anti-cancer activity against the CEM-SS cell line. This paper reports the isolation and identification of these compounds as well as bioassay data for the crude extracts, ${\gamma}-mangostin$ and rubraxanthone.

• Biomolecules & Therapeutics
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• 제25권6호
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• pp.609-617
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• 2017

Pancreatic cancer is one of the most lethal and aggressive cancers in the world. However, no effective treatment is currently available for pancreatic cancer. The objective of this study was to determine the anti-pancreatic cancer effect of ${\alpha}$-mangostin (${\alpha}M$) and ${\gamma}$-mangostin (${\gamma}M$) extracted from the pericarp of Garcinia mangostana L.. Both ${\alpha}$M and ${\gamma}M$ reduced the viability of pancreatic cancer cells MIA PaCa-2 and PANC-1 in a dose-dependent manner. These compounds induced apoptosis by increasing c-PARP and c-Caspase 3 levels. They also induced autophagy by increasing levels of microtubule-associated protein 1A/1B light chain 3B (LC3II) in both cell lines while decreasing sequestosome 1 (p62) in MIA PaCa-2. Both ${\alpha}$M and ${\gamma}M$ induced autophagy through increasing phosphorylation levels of AMP-activated protein kinase (p-AMPK) and p38-mitogen activated protein kinase (p-p38) while decreasing phosphorylation level of mammalian target of rapamycin complex 1 (p-mTOR). Of various microRNAs (miRNA), miR-18a was found to be a putative regulatory miRNA for autophagy induced by ${\alpha}$M or ${\gamma}M$. In combination with gemcitabine, a compound frequently used in pancreatic cancer treatment, ${\alpha}$M and ${\gamma}M$ showed synergistic anti-cancer effects in MIA PaCa-2. Collectively, these results suggest that ${\alpha}$M and ${\gamma}M$ can induce apoptosis and autophagy in pancreatic cancer cells and that their anti-cancer effect is likely to be associated with miR-18a. In conclusion, ${\alpha}$M and ${\gamma}M$ might be used as a potential new therapy for pancreatic cancer.