Daphnetin induced differentiation of human renal carcinoma cells and its mediation by p38 mitogen-activated protein kinase

Biochem Pharmacol. 2004 May 1;67(9):1779-88. doi: 10.1016/j.bcp.2004.01.014.


Daphnetin has been shown to be a potent in vitro anti-proliferative agent to the human renal cell carcinoma (RCC) cell line, A-498. In the present study, we investigated its effects on mitogen-activated protein kinase (MAPK) signalling along with cell cycle events and cellular differentiation. Daphnetin-activated p38, however, higher concentrations were required to inhibit ERK1/ERK2. In addition, it did not activate SAPK or induce apoptosis, but instead inhibited S phase cell cycle transition of A-498 cells at low concentrations and time of exposure. In addition, a late G(1), early S phase inhibition was observed at higher concentrations and time of exposure, indicating that the mechanism of daphnetin-induced differentiation was concentration dependent. Increased expression of the epithelial differentiation markers cytokeratins 8 and 18, correlated with increasing concentrations of daphnetin, while pre-treatment with a specific p38-inhibitor, served to limit this effect. There was no evidence that P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) played a role in the anti-proliferative activity of daphnetin. Consequently, we concluded that p38 MAP kinase is intrinsically involved in mediating the effect of daphnetin in A-498 cells, suggesting that this drug may act by promotion of cellular maturation, and consequently may represent a novel low toxic approach for the treatment of poorly differentiated RCCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Carcinoma, Renal Cell / pathology*
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects*
  • Drug Resistance, Multiple / drug effects
  • Humans
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Phosphorylation
  • Tumor Cells, Cultured
  • Umbelliferones / pharmacology*
  • p38 Mitogen-Activated Protein Kinases


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Umbelliferones
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • daphnetin