Investigation of intracellular signalling events mediating the mechanism of action of 7-hydroxycoumarin and 6-nitro-7-hdroxycoumarin in human renal cells.
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-NO2-7-OHC may represent a novel therapeutic agent for the treatment of RCC's.
Finn
Gregory J
GJ
National Centre for Sensor Research, Department of Applied Science, School of Science, Institute of Technology, Tallaght, Dublin 24, Ireland.
Creaven
Bernadette S
BS
Egan
Denise A
DA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D018432:Drug Resistance, Multiple; D006801:Humans; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014468:Umbelliferones / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003374:Coumarins; D014468:Umbelliferones; C031477:7-hydroxycoumarin; D020928:Mitogen-Activated Protein Kinases; D004250:DNA Topoisomerases, Type II