Gartanin

Nutr Cancer. 2013;65 Suppl 1:68-77.

The effect of gartanin, a naturally occurring xanthone in mangosteen juice, on the mTOR pathway, autophagy, apoptosis, and the growth of human urinary bladder cancer cell lines.[Pubmed: 23682785]

Androgen receptor (AR) has been a target of prostate cancer for nearly seven decades. In the last several years there has been an interest in identifying compounds that promote degradation of the androgen receptor. In the present study, Gartanin, an isoprentylated xanthone in the mangosteen fruit, was evaluated for enhancing AR degradation, and inducing the unfolded protein response pathway.
METHODS AND RESULTS:
The interaction of Gartanin with the ligand-binding domain was characterized using a fluorescence polarization cell-free assay and cell-based FRET assay. Western blot analysis identified modulation of ER stress markers (BiP, PERK, IRE1, and CHOP) along with androgen receptor degradation. A computation simulation was performed to identify possible orientations of Gartanin with the ligand-binding domain. Utilizing a cell-free and cell-based FRET assays Gartanin was found to interact with the ligand-binding domain through a solely antagonist interaction. Interestingly, inhibition of CHOP, a critical component of the ER stress pathway, was observed to stabilize AR.
CONCLUSIONS:
Gartanin is an isoprenylated xanthone that promotes AR degradation with evidence suggesting this process is critically regulated by the unfolded protein response pathway.

J Cell Mol Med. 2017 Jan;21(1):46-57.

Gartanin induces cell cycle arrest and autophagy and suppresses migration involving PI3K/Akt/mTOR and MAPK signalling pathway in human glioma cells.[Pubmed: 27491646 ]

In central nervous system, glioma is the most common primary brain tumour. The diffuse migration and rapid proliferation are main obstacles for successful treatment.
METHODS AND RESULTS:
Gartanin, a natural xanthone of mangosteen, suppressed proliferation, migration and colony formation in a time- and concentration-dependent manner in T98G glioma cells but not in mouse normal neuronal HT22 cells. Gartanin, at low micromole, led to cell cycle arrest in G1 phase accompanied by inhibited expression level of G1 cell cycle regulatory proteins cyclin D1, while increased expression level of cyclin-dependent kinase inhibitor p27Kip1. In addition, the secretion and activity of matrix metalloproteinases 2/9 (MMP-2/-9) were significantly suppressed in T98G cells treated with Gartanin, and it might result from modulating mitogen-activated protein kinases (MAPK) signalling pathway in T98G glioma cells. Moreover, Gartanin significantly induced autophagy in T98G cells and increased GFP-LC3 punctate fluorescence accompanied by the increased expression level of Beclin 1 and LC3-II, while suppressed expression level of p62. Gartanin treatment resulted in obvious inhibition of PI3K/Akt/mTOR signalling pathway, which is important in modulating autophagy. Notably, Gartanin-mediated anti-viability was significantly abrogated by autophagy inhibitors including 3-methyladenine (3-MA) and chloroquine (CQ).
CONCLUSIONS:
These results indicate that anti-proliferation effect of Gartanin in T98G cells is most likely via cell cycle arrest modulated by autophagy, which is regulated by PI3K/Akt/mTOR signalling pathway, while anti-migration effect is most likely via suppression of MMP-2/-9 activity which is involved in MAPK signalling pathway.

Oncol Rep. 2015 Jul;34(1):139-46.

Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis.[Pubmed: 25955534]

Gartanin, a xanthone-type compound isolated from mangosteen, is known to possess potent antioxidant, anti‑inflammatory, antifungal and antineoplastic properties.
METHODS AND RESULTS:
In the present study, we investigated the cytotoxic effect of Gartanin on HCC and explored the cell death mechanism. We showed that Gartanin induced both the extrinsic and intrinsic apoptotic pathways, which were interconnected by caspase-8, -9 and -3 activation. We also provided convincing evidence that Gartanin induced autophagy in various cancer cells, as demonstrated by acridine orange staining of intracellular acidic vesicles, the degradation of p62, the conversion of LC3-I to LC3-II and GFP-LC3 punctate fluorescence. Additionally, Gartanin induced the formation of typical autophagosomes and autolysosomes and enhanced the degradation rate of intracellular granule(s), including mitochondria. Notably, Gartanin-mediated apoptotic cell death was further potentiated by pretreatment with autophagy inhibitors (3-methyladenine and bafilomycin A1) or small interfering RNAs against the autophagic genes (Atg5). These findings suggested that Gartanin-mediated autophagic response protected against eventual cell death induced by Gartanin. Moreover, Gartanin treatment led to phosphorylation/activation of JNK and JNK-dependent phosphorylation of Bcl-2. Importantly, JNK inhibitor (SP600125) inhibited autophagy yet promoted Gartanin-induced apoptosis, indicating a key requirement of the JNK-Bcl-2 pathway in the activation of autophagy by Gartanin.
CONCLUSIONS:
Taken together, our data suggested that the JNK-Bcl-2 pathway was the critical regulator of Gartanin-induced protective autophagy and a potential drug target for chemotherapeutic combination.

Mol Nutr Food Res. 2016 Jun;60(6):1458-69.

Gartanin, an isoprenylated xanthone from the mangosteen fruit (Garcinia mangostana), is an androgen receptor degradation enhancer.[Pubmed: 27019217]

Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities.
METHODS AND RESULTS:
Herein, the neuroprotection capacity of Gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1-10 μM Gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that Gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that Gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of Gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after Gartanin treatment.
CONCLUSIONS:
Taken together, these findings suggest Gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways.

Neurochem Res. 2016 Sep;41(9):2267-77.

Gartanin Protects Neurons against Glutamate-Induced Cell Death in HT22 Cells: Independence of Nrf-2 but Involvement of HO-1 and AMPK.[Pubmed: 27161377 ]

Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities.
METHODS AND RESULTS:
Herein, the neuroprotection capacity of Gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1-10 μM Gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that Gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that Gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of Gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after Gartanin treatment.
CONCLUSIONS:
Taken together, these findings suggest Gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways.