Cytotoxic and antitumor effects of brucine on Ehrlich ascites tumor and human cancer cell line

Life Sci. 2011 Aug 1;89(5-6):147-58. doi: 10.1016/j.lfs.2011.05.020. Epub 2011 Jun 13.

Abstract

Aims: Brucine (BRU), a natural plant alkaloid is reported to possess cytotoxic and antiproliferative activities. In this study we aimed to investigate its in vitro and in vivo antitumor and antiangiogenic effects.

Main methods: Cell proliferation and viability was assessed using microculture tetrazolium tests (MTT). As predictive markers we determined intracellular levels of vascular endothelial growth factor (VEGF), Interleukin-12 (IL-12), tumor necrosis factor (TNF-α), caspase-3, -8 and -9 by ELISA and enzymatic activity assays. In addition, anti-VEGF neutralization effect was evaluated to assess whether it could result in augmented anticancer efficacy than the single agent. Antitumor activity was evaluated against Ehrlich ascites and solid tumor models. 15×10(6) EAC cells were implanted intraperitoneally (i.p., ascites tumor) and subcutaneous (s.c., solid tumor) in Swiss albino mice. Mice with established tumors received brucine i.p. at 12.5, 25, and 50mg/kg for 14days in ascites tumor and 50mg/kg in solid tumor for 30days. Tumor volume, cell viability, angiogenic, anti-angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF and CD-31 was also performed.

Key findings: BRU produced time and dose-dependent inhibition of MCF-7 in vitro and EAC tumors in vivo. The anti-angiogenic effects were accompanied with decreased VEGF and TNF-α and increased IL-12 expression. BRU reduced peritoneal angiogenesis and microvessel density in vivo.

Conclusion: Our findings suggest that BRU possesses antitumor and anti-angiogenic activities in vitro and in vivo. The above results showed that BRU can be used as a potential anticancer agent as an antimetastatic and anti-angiogenic agent.

MeSH terms

  • Animals
  • Antineoplastic Agents*
  • Antioxidants / metabolism
  • Blood Cell Count
  • Carcinoma, Ehrlich Tumor / blood supply
  • Carcinoma, Ehrlich Tumor / drug therapy*
  • Carcinoma, Ehrlich Tumor / pathology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Immunohistochemistry
  • Interleukin-12 / analysis
  • Interleukin-12 / metabolism
  • Mice
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / pathology
  • Oxidative Stress / drug effects
  • Strychnine / analogs & derivatives*
  • Strychnine / pharmacology
  • Survival Analysis
  • Tetrazolium Salts
  • Thiazoles
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / analysis
  • Vascular Endothelial Growth Factor A / metabolism
  • bcl-2-Associated X Protein / biosynthesis
  • bcl-2-Associated X Protein / genetics

Substances

  • Antineoplastic Agents
  • Antioxidants
  • Tetrazolium Salts
  • Thiazoles
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • bcl-2-Associated X Protein
  • Interleukin-12
  • brucine
  • Caspases
  • thiazolyl blue
  • Strychnine