TY - JOUR
T1 - Investigation of intracellular signalling events mediating the mechanism of action of 7-hydroxycoumarin and 6-nitro-7-hdroxycoumarin in human renal cells
AU - Finn, Gregory J.
AU - Creaven, Bernadette S.
AU - Egan, Denise A.
PY - 2004/3/8
Y1 - 2004/3/8
N2 - Previously, 7-hydroxycoumarin (7-OHC) and 6-nitro-7-hydroxycoumarin (6-NO2-7-OHC) have been shown to be potent and selective anti-proliferative agents to the human renal cell carcinoma (RCC) cell line, A-498. Their effect on mitogen-activated protein kinases (MAPK's) was investigated. 6-NO2-7-OHC was shown to alter the phosphorylation status of ERK1/ERK2, p38 and SAPK, while 7-OHC activated ERK1/ERK2 but had no effect on p38 and SAPK. Also, 7-OHC inhibited topoisomerase II mediated relaxation of DNA, while neither compound was a substrate for P-glycoprotein (P-gp) mediated multi-drug resistance (MDR). Therefore, 6-NO2-7-OHC, rather than 7-OHC, modulated signalling events associated with cellular differentiation and apoptosis, suggesting its mechanism of action may be the promotion of cellular maturation and/or death. Consequently, 6-NO 2-7-OHC may represent a novel therapeutic agent for the treatment of RCC's.
AB - Previously, 7-hydroxycoumarin (7-OHC) and 6-nitro-7-hydroxycoumarin (6-NO2-7-OHC) have been shown to be potent and selective anti-proliferative agents to the human renal cell carcinoma (RCC) cell line, A-498. Their effect on mitogen-activated protein kinases (MAPK's) was investigated. 6-NO2-7-OHC was shown to alter the phosphorylation status of ERK1/ERK2, p38 and SAPK, while 7-OHC activated ERK1/ERK2 but had no effect on p38 and SAPK. Also, 7-OHC inhibited topoisomerase II mediated relaxation of DNA, while neither compound was a substrate for P-glycoprotein (P-gp) mediated multi-drug resistance (MDR). Therefore, 6-NO2-7-OHC, rather than 7-OHC, modulated signalling events associated with cellular differentiation and apoptosis, suggesting its mechanism of action may be the promotion of cellular maturation and/or death. Consequently, 6-NO 2-7-OHC may represent a novel therapeutic agent for the treatment of RCC's.
KW - 6-Nitro-7-hydroxycoumarin
KW - In vitro
KW - Mitogen-activated protein kinase
KW - Renal cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=1242293659&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2003.09.024
DO - 10.1016/j.canlet.2003.09.024
M3 - Article
C2 - 15036663
AN - SCOPUS:1242293659
SN - 0304-3835
VL - 205
SP - 69
EP - 79
JO - Cancer Letters
JF - Cancer Letters
IS - 1
ER -