title: α-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.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  Mammary 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.
  
  
  RESULTS
  Not 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.
  
  
  CONCLUSIONS
  Since 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.
authors.affiliation: Laboratory of Anatomy and Histopathology, Faculty of Health Science, Osaka Health Science University, Osaka, Japan. masaaki.shibata@ohsu.ac.jp
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Shibata
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.forename: Junji
authors.initials: J
authors.lastname: Morimoto
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kurose
authors.forename: Kanako
authors.initials: K
authors.lastname: Akamatsu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okuno
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D029762:Garcinia mangostana / Q000737:chemistry*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044004:Xanthones / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D044004:Xanthones; C021053:mangostin