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A sesquiterpenelactone from Inula britannica induces anti-tumor effects dependent on Bcl-2 phosphorylation.

AbstractBACKGROUND:
The over-expression of the anti-apoptotic protein Bcl-2 in cancer is associated with resistance to chemotherapeutic drugs. The phosphorylation of Bcl-2 is one mechanism by which anti-microtubule agents, such as paclitaxel or docetaxel, may inactivate Bcl-2. Although initially active in clinical studies, current anti-microtubule agents are only temporarily effective and the discovery of new agents is warranted.
MATERIALS AND METHODS:
We isolated and identified two known sesquiterpenelactones, O, O-diacetylbritannilactone (OODABL) and O-acetylbritaanilactone (OABL) from the flowers of the medicinal plant Inula britannica and studied their mechanism of anti-tumor effects. To determine the biological significance of Bcl-2 phosphorylation, we used a baby rat kidney (BRK-p53) cell line that was transformed with EIA and a temperature-sensitive mutant p53. The BRK-p53 cell line was transfected with either a vector with wild type Bcl-2 or a vector in which Bcl-2 had mutations in the paclitaxel phosphorylation sites (pcDNA3.1 V5/His Bcl-2 S70, 87A).
RESULTS:
OODABL and OABL induced phosphorylation of Bcl-2 in breast, ovary and prostate cancer cell lines and induced G2/M cell cycle arrest. Using the BRK cells with mutant Bcl-2 (BRK-Bcl-2-mt) and control (BRK-Bcl-2-wt), we found that OODABL induced phosphorylation of Bcl-2 at sites similar to paclitaxel. Phosphorylation of Bcl-2 was important for OODABL-induced cytotoxicity, since the abrogation of phosphorylation in BRK-Bcl-2-mt cells decreased OODABL-induced cytotoxicity.
CONCLUSION:
We concluded that OODABL is cytotoxic in multiple tumor cell lines, and the cytotoxicity is dependent, at least in part, on the phosphorylation of Bcl-2.
AuthorsMohamed M Rafi, Nai-Sheng Bai, Chi-Tang-Ho, Robert T Rosen, Eileen White, Denise Perez, Robert S Dipaola
JournalAnticancer research (Anticancer Res) 2005 Jan-Feb Vol. 25 Issue 1A Pg. 313-8 ISSN: 0250-7005 [Print] Greece
PMID15816553 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Lactones
  • O, O-diacetylbritannilactone
  • O-acetylbritaanilactone
  • Proto-Oncogene Proteins c-bcl-2
  • Sesquiterpenes
Topics
  • Animals
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Flowers (chemistry)
  • Humans
  • Inula (chemistry)
  • Lactones (isolation & purification, pharmacology)
  • Mutagenesis, Site-Directed
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
  • Rats
  • Sesquiterpenes (isolation & purification, pharmacology)

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