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

Mohamed M. Rafi, Nai Sheng Bai, Chi-Tang-Ho, Robert T. Rosen, Eileen White, Denise Perez, Robert S. Dipaola

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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 E1A 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 VS/His Bcl-2 S70, 87 A). 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.

Original languageEnglish
Pages (from-to)313-318
Number of pages6
JournalAnticancer Research
Volume25
Issue number1 A
StatePublished - Jan 2005

Keywords

  • Anti-tumor
  • Apoptotic proteins
  • Bcl-2
  • Bcl-2 phosphorylation
  • Sesquiterpenelactones
  • Taxol

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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