α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostanaLinn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation

Abstract

BackgroundThe 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.MethodsMammary 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.ResultsNot 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.ConclusionsSince 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.

Extraction of Xanthones from the Pericarps of <i>Garcinia mangostana</i> Linn. with Supercritical Carbon Dioxide and Ethanol

“…The chemical structures of 8 major xanthones contained in pericarps are shown in Figure 1. They have been attracting much attention because of their pharmacological activity, such as anti-allergy [6], anti-bacterial [7,8], anti-tumoral [9,10], anti-inflammatory [11], anti-oxidant [12][13][14] and anti-hypertensive properties [15]. Also, they were observed to induce apoptosis by targeting mitochondria of a decreased membrane potential, leading to the activation of the intrinsic apoptotic signal transduction [16].…”

Development and Validation of Analytical Method by RP-HPLC for Quantification of Alpha-Mangostin Encapsulated in PLGA Microspheres

“…It is well known that alpha-mangostin exhibited a broad spectrum of biological effects including anti-oxidant [8], anti-inflammatory [9], anti-allergic [10], analgesic [11], neuro-protective [12], anti-mycobacterial [1], antifungal [13], anti-bacterial [14] and anti-proliferative [15,16] activities. In addition, recent studies have indicated that alpha-mangostin had anti-metastatic effect against various cancer cell lines [17][18][19]. Nevertheless, the results of pharmacokinetic study of pure alphamangostin revealed its low oral bioavailability attributed to the first pass metabolism beside its non-selective distribution into the rat tissue [20].…”

“…The chromatographic separation was performed at ambient temperature using Hypersil  BDS C 18 column (4.6×100 mm, 3 μm) with C 18 …”

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“…Phosphorylated and total ERK, JNK, and Akt were downregulated in α-MG-treated SW1353 cells, but there were no changes in p38 MAPK [88]. In both mammary carcinoma cells in culture and tissues in vivo, α-MG significantly decreased the levels of phospho-Akt-Thr308 [27]. In addition, there is substantial evidence that α-MG restrained the process of invasion and migration in cancer cells by acting on the MAPK or Akt pathway.…”

“…Importantly, besides the inhibitory effects on the growth of primary tumors, α-MG has also shown significant antimetastatic effects in animal models. Shibata et al [27] successfully developed a metastatic cancer model by implanting murine mammary adenocarcinoma BJMC3879luc2 cells into syngeneic BALB/c mice, which induces a metastatic spectrum similar to that seen in human breast cancer. Using this model, they confirmed that α-MG significantly attenuated the growth of tumors and the multiplicity of lymph node metastasis.…”