Abstract | BACKGROUND: 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.
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Authors | Mohamed M Rafi, Nai-Sheng Bai, Chi-Tang-Ho, Robert T Rosen, Eileen White, Denise Perez, Robert S Dipaola |
Journal | Anticancer research
(Anticancer Res)
2005 Jan-Feb
Vol. 25
Issue 1A
Pg. 313-8
ISSN: 0250-7005 [Print] Greece |
PMID | 15816553
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Lactones
- O, O-diacetylbritannilactone
- O-acetylbritaanilactone
- Proto-Oncogene Proteins c-bcl-2
- Sesquiterpenes
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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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