The natural compound n-butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo

J Neurochem. 2006 Nov;99(4):1251-62. doi: 10.1111/j.1471-4159.2006.04151.x. Epub 2006 Sep 20.

Abstract

The naturally-occurring compound, n-butylidenephthalide (BP), which is isolated from the chloroform extract of Angelica sinensis (AS-C), has been investigated with respect to the treatment of angina. In this study, we have examined the anti-tumor effects of n-butylidenephthalide on glioblastoma multiforme (GBM) brain tumors both in vitro and in vivo. In vitro, GBM cells were treated with BP, and the effects of proliferation, cell cycle and apoptosis were determined. In vivo, DBTRG-05MG, the human GBM tumor, and RG2, the rat GBM tumor, were injected subcutaneously or intracerebrally with BP. The effects on tumor growth were determined by tumor volumes, magnetic resonance imaging and survival rate. Here, we report on the potency of BP in suppressing growth of malignant brain tumor cells without simultaneous fibroblast cytotocixity. BP up-regulated the expression of Cyclin Kinase Inhibitor (CKI), including p21 and p27, to decrease phosphorylation of Rb proteins, and down-regulated the cell-cycle regulators, resulting in cell arrest at the G(0)/G(1) phase for DBTRG-05MG and RG2 cells, respectively. The apoptosis-associated proteins were dramatically increased and activated by BP in DBTRG-05MG cells and RG2 cells, but RG2 cells did not express p53 protein. In vitro results showed that BP triggered both p53-dependent and independent pathways for apoptosis. In vivo, BP not only suppressed growth of subcutaneous rat and human brain tumors but also, reduced the volume of GBM tumors in situ, significantly prolonging survival rate. These in vitro and in vivo anti-cancer effects indicate that BP could serve as a new anti-brain tumor drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / physiopathology
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p27 / drug effects
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Drugs, Chinese Herbal / pharmacology*
  • Drugs, Chinese Herbal / therapeutic use
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology
  • Glioblastoma / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • NIH 3T3 Cells
  • Phthalic Anhydrides / pharmacology*
  • Phthalic Anhydrides / therapeutic use
  • Rats
  • Resting Phase, Cell Cycle / drug effects
  • Resting Phase, Cell Cycle / genetics
  • Survival Rate
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • Drugs, Chinese Herbal
  • Phthalic Anhydrides
  • angelicae sinensis extract
  • Cyclin-Dependent Kinase Inhibitor p27
  • butylidenephthalide