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

Gregory J. Finn, Bernadette S. Creaven, Denise A. Egan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 G1, 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.

    Original languageEnglish
    Pages (from-to)1779-1788
    Number of pages10
    JournalBiochemical Pharmacology
    Volume67
    Issue number9
    DOIs
    Publication statusPublished - 1 May 2004

    Keywords

    • DMEM
    • DMSO
    • Dimethylsulphoxide
    • Dulbecco's modified Eagle's medium
    • ERK
    • Extracellular signal related kinase
    • MAPK
    • MDR
    • Mitogen-activated protein kinase
    • Multi-drug resistence
    • P-glycoprotein
    • P-gp
    • RCC
    • Renal cell carcinoma
    • SAPK
    • Stress-activated protein kinase

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