Celecoxib and acetylbritannilactone interact synergistically to suppress breast cancer cell growth via COX-2-dependent and -independent mechanisms

Cell Death Dis. 2011 Jul 28;2(7):e185. doi: 10.1038/cddis.2011.64.


The use of celecoxib is associated with a significant decrease in breast cancer risk. However, the long-term use of high-dose celecoxib might be limited owing to cardiovascular side effects. In this study, we found that acetylbritannilactone (ABL), extract from a Chinese medicinal herb, could reduce celecoxib dose and potentiate the growth-inhibitory effect in breast cancer cells. ABL enhanced the apoptotic effect of celecoxib in COX-2-expressing cells, but had little effect in COX-2-negative cells. The apoptosis induced by the combination treatment disappeared when COX-2 was knocked down, whereas the lack of apoptotic effects in COX-2-negative cells was reversed after COX-2 transfection. However, the combination treatment induced a G(0)/G(1) phase arrest independent of whether or not the cells expressed COX-2. The G(0)/G(1) arrest was attributed to a decreased expression of cyclinD1, cyclinE, CDK2 and CDK6, especially the upregulation of p21. In addition, inhibition of Akt and p38 signaling pathways was required by the synergism, as the constitutively active Akt and p38 protected cells against apoptosis and cell cycle arrest induced by the combination treatment. In vivo, administration of celecoxib and ABL were more effective than the individual agents against xenograft tumor growth. Thus, our data suggested that the combinatorial approach of celecoxib and ABL might be helpful for breast cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Celecoxib
  • Cell Line, Tumor
  • Cyclin D1 / metabolism
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase 6 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclooxygenase 2 / chemistry
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / therapeutic use
  • Cyclooxygenase 2 Inhibitors / toxicity*
  • Drugs, Chinese Herbal / therapeutic use
  • Drugs, Chinese Herbal / toxicity*
  • Female
  • G1 Phase
  • Humans
  • Lactones / therapeutic use
  • Lactones / toxicity*
  • Mice
  • Mice, Nude
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / therapeutic use
  • Pyrazoles / toxicity*
  • Resting Phase, Cell Cycle
  • Signal Transduction
  • Sulfonamides / therapeutic use
  • Sulfonamides / toxicity*
  • Transplantation, Heterologous
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclooxygenase 2 Inhibitors
  • Drugs, Chinese Herbal
  • Lactones
  • Pyrazoles
  • Sulfonamides
  • acetylbritannilatone
  • Cyclin D1
  • Cyclooxygenase 2
  • Proto-Oncogene Proteins c-akt
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 6
  • p38 Mitogen-Activated Protein Kinases
  • Celecoxib