alpha-Mangostin

Biochem Biophys Res Commun. 2014 Oct 10;453(1):75-80.

Inhibition of CHOP accentuates the apoptotic effect of α-mangostin from the mangosteen fruit (Garcinia mangostana) in 22Rv1 prostate cancer cells.[Pubmed: 25261723]

The mangosteen (Garcinia mangostana) fruit has been a popular food in Southeast Asia for centuries and is increasing in popularity in Western countries.
METHODS AND RESULTS:
We identified alpha-Mangostin as a primary phytochemical modulating ER stress proteins in prostate cancer cells and propose that alpha-Mangostin is responsible for exerting a biological effect in prostate cancer cells. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two patients undergoing radical prostatectomy were treated with alpha-Mangostin and evaluated by RT-PCR, Western blot, fluorescent microscopy and siRNA transfection to evaluate ER stress. Next, we evaluated alpha-Mangostin for microsomal stability, pharmacokinetic parameters, and anti-cancer activity in nude mice. alpha-Mangostin significantly upregulated ER stress markers in prostate cancer cells. Interestingly, alpha-Mangostin did not promote ER stress in prostate epithelial cells (PrECs) from prostate cancer patients. CHOP knockdown enhanced alpha-Mangostin-induced apoptosis in prostate cancer cells. alpha-Mangostin significantly suppressed tumor growth in a xenograft tumor model without obvious toxicity.
CONCLUSIONS:
Our study suggests that alpha-Mangostin is not the only active constituent from the mangosteen fruit requiring further work to understand the complex chemical composition of the mangosteen.

Evid Based Complement Alternat Med. 2015;2015:740238.

α-Mangostin Improves Glucose Uptake and Inhibits Adipocytes Differentiation in 3T3-L1 Cells via PPARγ, GLUT4, and Leptin Expressions.[Pubmed: 25873982]

Obesity has been often associated with the occurrence of cardiovascular diseases, type 2 diabetes, and cancer. The development of obesity is also accompanied by significant differentiation of preadipocytes into adipocytes.
METHODS AND RESULTS:
In this study, we investigated the activity of alpha-Mangostin, a major xanthone component isolated from the stem bark of G. malaccensis, on glucose uptake and adipocyte differentiation of 3T3-L1 cells focusing on PPARγ, GLUT4, and leptin expressions. alpha-Mangostin was found to inhibit cytoplasmic lipid accumulation and adipogenic differentiation. Cells treated with 50 μM of alpha-Mangostin reduced intracellular fat accumulation dose-dependently up to 44.4% relative to MDI-treated cells. Analyses of 2-deoxy-D-[(3)H] glucose uptake activity showed that alpha-Mangostin significantly improved the glucose uptake (P < 0.05) with highest activity found at 25 μM. In addition, alpha-Mangostin increased the amount of free fatty acids (FFA) released. The highest glycerol release level was observed at 50 μM of alpha-Mangostin. qRT-PCR analysis showed reduced lipid accumulation via inhibition of PPARγ gene expression. Induction of glucose uptake and free fatty acid release by alpha-Mangostin were accompanied by increasing mRNA expression of GLUT4 and leptin.
CONCLUSIONS:
These evidences propose that alpha-Mangostin might be possible candidate for the effective management of obesity in future.

J Pharmacol Sci. 2004 May;95(1):33-40.

Alpha-mangostin induces Ca2+-ATPase-dependent apoptosis via mitochondrial pathway in PC12 cells.[Pubmed: 15153648]

We investigated the cell death effects of eight xanthones on PC12 rat pheochromocytoma cells.
METHODS AND RESULTS:
Among these compounds, alpha-Mangostin, from the fruit hull of Garcinia mangostana L., had the most potent effect with the EC(50) value of 4 microM. alpha-Mangostin-treated PC12 cells demonstrated typical apoptotic DNA fragmentation and caspase-3 cleavage (equivalent to activation). The flow cytometric analysis indicated that this compound induced apoptosis in time-and concentration-dependent manners. alpha-Mangostin showed the features of the mitochondrial apoptotic pathway such as mitochondrial membrane depolarization and cytochrome c release. Furthermore, alpha-Mangostin inhibited the sarco(endo)plasmic reticulum Ca(2+)-ATPase markedly. There was a correlation between the Ca(2+)-ATPase inhibitory effects and the apoptotic effects of the xanthone derivatives. On the other hand, c-Jun NH(2)-terminal kinase (JNK/SAPK), one of the signaling molecules of endoplasmic reticulum (ER) stress, was activated with alpha-Mangostin treatment.
CONCLUSIONS:
These results suggest that alpha-Mangostin inhibits Ca(2+)-ATPase to cause apoptosis through the mitochondrial pathway.

Bioorg Med Chem. 2004 Nov 15;12(22):5799-806.

Preferential target is mitochondria in alpha-mangostin-induced apoptosis in human leukemia HL60 cells.[Pubmed: 15498656]

Our previous study has shown that alpha-Mangostin, a xanthone from the pericarps of mangosteen, induces caspase-3-dependent apoptosis in HL60 cells. In the current study, we investigated the mechanism of apoptosis induced by alpha-Mangostin in HL60 cells.
METHODS AND RESULTS:
alpha-Mangostin-treated HL60 cells demonstrated caspase-9 and -3 activation but not -8, which leads us to assume that alpha-Mangostin may mediate the mitochondrial pathway in the apoptosis. Parameters of mitochondrial dysfunction including swelling, loss of membrane potential (deltapsim), decrease in intracellular ATP, ROS accumulation, and cytochrome c/AIF release, were observed within 1 or 2 h after the treatment. On the other hand, alpha-Mangostin-treatment did not affect expression of bcl-2 family proteins and activation of MAP kinases. These findings indicate that alpha-Mangostin preferentially targets mitochondria in the early phase, resulting in indication of apoptosis in HL60 cells. Furthermore, we examined the structure-activity relationship between xanthone derivatives including alpha-Mangostin and the potency of deltapsim-loss in HL60 cells. Interestingly, replacement of hydroxyl group by methoxy group remarkably decreased its potency. It was also shown that the cytotoxicity substantially correlated with deltapsim decrease.
CONCLUSIONS:
These results indicate that alpha-Mangostin and its analogs would be candidates for preventive and therapeutic application for cancer treatment.

Cell Biochem Biophys. 2010 Sep;58(1):31-44.

Alpha-mangostin suppresses phorbol 12-myristate 13-acetate-induced MMP-2/MMP-9 expressions via alphavbeta3 integrin/FAK/ERK and NF-kappaB signaling pathway in human lung adenocarcinoma A549 cells.[Pubmed: 20652762]

The purpose of this study is to investigate the anti-metastatic effect of alpha-Mangostin on phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expressions in A549 human lung adenocarcinoma cells.
METHODS AND RESULTS:
Firstly, alpha-Mangostin could inhibit PMA-induced abilities of the adhesion, invasion, and migration. Data also showed alpha-Mangostin could inhibit the activation of alphavbeta3 integrin, focal adhesion kinase (FAK), and extracellular signal-regulated kinase1/2 (ERK1/2) involved in the downregulation the enzyme activities, protein and messenger RNA levels of MMP-2 and MMP-9 induced by PMA. Next, alpha-Mangostin also strongly inhibited PMA-induced degradation of inhibitor of kappaBalpha (IkappaBalpha) and the nuclear levels of nuclear factor kappa B (NF-kappaB). Also, a dose-dependent inhibition on the binding abilities of NF-kappaB by alpha-Mangostin treatment was further observed. Furthermore, reduction of FAK or ERK1/2 phosphorylation by FAK small interfering RNA (FAK siRNA) potentiated the effect of alpha-Mangostin. Finally, the transient transfection of ERK siRNA significantly down-regulated the expressions of MMP-2 and MMP-9 concomitantly with a marked inhibition on cell invasion and migration.
CONCLUSIONS:
Presented results indicated alpha-Mangostin is a novel, effect, anti-metastatic agent that functions by downregulating MMP-2 and MMP-9 gene expressions.

Eur J Pharmacol. 1996 Oct 31;314(3):351-6.

Pharmacological properties of alpha-mangostin, a novel histamine H1 receptor antagonist.[Pubmed: 8957258]

METHODS AND RESULTS:
In the isolated rabbit thoracic aorta and guinea-pig trachea, alpha-Mangostin inhibited histamine-induced contractions in a concentration-dependent manner in the presence or absence of cimetidine, a histamine H2 receptor antagonist. But KCl-, phenylephrine- or carbachol-induced contractions were not affected by alpha-Mangostin. The concentration-contractile response curve for histamine was shifted to the right in a parallel manner by alpha-Mangostin. In the presence of chlorpheniramine, a histamine H1 receptor antagonist, alpha-Mangostin did not affect the relaxation of the rabbit aorta induced by histamine. In the guinea-pig trachea, alpha-Mangostin had no effect on the relaxation induced by dimaprit, a histamine H2 receptor agonist. alpha-Mangostin caused a concentration-dependent inhibition of the binding of [3H]mepyramine, a specific histamine H1 receptor antagonist to rat aortic smooth muscle cells. Kinetic analysis of [3H]mepyramine binding indicated the competitive inhibition by alpha-Mangostin.
CONCLUSIONS:
These results suggest that alpha-Mangostin is a novel competitive histamine H1 receptor antagonist in smooth muscle cells.

Exp Toxicol Pathol. 2009 Sep;61(5):491-501.

ROS scavenging capacity and neuroprotective effect of alpha-mangostin against 3-nitropropionic acid in cerebellar granule neurons.[Pubmed: 19108999 ]

alpha-Mangostin is a xanthone with antioxidant properties isolated from mangosteen fruit. The reactive oxygen species (ROS) scavenging capacity and the potential protective effect of alpha-Mangostin against the mitochondrial toxin 3-nitropropionic acid (3-NP) in primary cultures of cerebellar granule neurons (CGNs) were studied in the present work. It was found that alpha-Mangostin was able to scavenge in a concentration-dependent way singlet oxygen, superoxide anion and peroxynitrite anion. In contrast, alpha-Mangostin was unable to scavenge hydroxyl radicals and hydrogen peroxide. Furthermore, alpha-Mangostin was able to ameliorate in a concentration-dependent way the neuronal death induced by 3-NP. This protective effect was associated with an amelioration of 3-NP-induced reactive oxygen species formation.
CONCLUSIONS:
It is concluded that alpha-Mangostin is able to scavenge directly several ROS and has a neuroprotective effect against 3-NP in primary cultures of CGNs, which is associated with its ability to ameliorate 3-NP-induced ROS production.

Biol Res Nurs. 2015 Jan;17(1):68-77.

Mechanisms of α-mangostin-induced antinociception in a rodent model.[Pubmed: 25504952 ]

Elucidate the antinociceptive mechanisms of alpha-Mangostin isolated from Garcinia malaccensis Linn.
METHODS AND RESULTS:
Male mice/rats (n = 6/group) were used in this between-group study. To determine α-mangostin's antinociceptive profile, animals were given alpha-Mangostin orally (3, 30, or 100 mg/kg) 60 min before the start of the abdominal constriction or formalin tests. To explore alpha-Mangostin's mechanisms of action, we performed (i) the hot plate test with naloxone (5 mg/kg) pretreatment to verify involvement of opioid receptors; (ii) the abdominal constriction test with 20 mg/kg l-arginine, N(G)-nitro-l-arginine methyl esters (l-NAME), methylene blue (MB), l-arginine plus l-NAME, or l-arginine plus MB or 10 mg/kg glibenclamide pretreatment to verify involvement of the l-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) and K -ATP pathways; and (iii) the paw-licking test using capsaicin (1.6 μg capsaicin/paw), glutamate (10 μmol glutamate/paw), or phorbol 12-myristate 13-acetate (PMA; 0.05 µg/paw) to verify involvement of vanilloid receptors, the glutamatergic system, and protein kinase C (PKC). RESULTS: alpha-Mangostin significantly inhibited nociception (p < .05) in all models. Only naloxone, l-arginine, methylene blue, PMA, and glibenclamide affected alpha-Mangostin antinociception significantly (p < .05).
CONCLUSIONS:
alpha-Mangostin exhibits peripheral and central antinociception through modulation of opioid and vanilloid receptors, the glutamatergic system, and the l-arginine/NO/cGMP/PKC/K( )-ATP pathways.