Research: SHIBATA and COLLEAGUES,

Listed in Issue 205

Abstract

SHIBATA and COLLEAGUES,  Laboratory of Anatomy and Histopathology, Faculty of Health Science, Osaka Health Science University, Osaka, Japan. masaaki.shibata@ohsu.ac.jp investigated the antitumour growth and antimetastatic activities of alpha-mangostin in an xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers.

Background

The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound alpha-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 antitumour growth and antimetastatic activities of alpha-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.

Methodology

Mammary tumours, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with alpha-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumour ability by alpha-mangostin, in vitro studies were also conducted.

Results

Not only were in vivo survival rates significantly higher in the 20 mg/kg/day alpha-mangostin group versus controls, but both tumour volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumours 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 tumour cells in mammary carcinoma tissues. In vitro, alpha-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 alpha-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that alpha-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.

Conclusion

Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of alpha-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, alpha-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.

References

Shibata MA, Iinuma M, Morimoto J, Kurose H, Akamatsu K, Okuno Y, Akao Y and Otsuki Y. alpha-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation. Source BMC Medicine. 9:69, 2011. Other ID Source: NLM. PMC3121600. 2011.

Comment

The above research appears to indicate several highly promising anti-tumour properties of alpha-mangostin, including apoptosis, survival rate, tumour volume and multiplicity of lymph node metastases.

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