Flavone acetic acid potentiates the induction of endothelial procoagulant activity by tumour necrosis factor.
Treatment of human umbilical vein endothelial cells with flavone acetic acid (FAA) at 800 micrograms/ml for 4 h resulted in a 3-11-fold increase in procoagulant activity. This increase was due to enhanced tissue factor expression on the endothelial cell surface, as evidenced by the blocking of the enhanced clotting with antibody to tissue factor, by substitution of normal with factor VII deficient plasma, or by simultaneous treatment of the endothelial cells with cycloheximide or actinomycin D. FAA was not toxic to endothelial cell at concentrations up to 1.6 mg/ml over 4 h. Combined treatment with FAA and tumour necrosis factor alpha (TNF-alpha) (100 pg/ml) produced a 675-fold (range 160-1980) increase in tissue factor activity, compared to 5-fold and 50-fold increases for the individual agents respectively. Northern blotting of total RNA from cells treated with the combination of agents or either agent alone, followed by probing with a cDNA to human tissue factor demonstrated a synergistic increase in tissue factor mRNA after combination treatment. In vivo, the combination of FAA and TNF-alpha could be shown to induce greater growth delay in two murine tumours than would be predicted on the basis of the activity of either agent alone.
Murray
J C
JC
CRC Gray Laboratory, Mt Vernon Hospital, Northwood, Mddx, U.K.
Smith
K A
KA
Stern
D M
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015152:Blotting, Northern; D002478:Cells, Cultured; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013925:Thromboplastin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005419:Flavonoids; D014409:Tumor Necrosis Factor-alpha; C049328:flavone acetic acid; D013925:Thromboplastin