A protein kinase C inhibitor NA-382 prolongs the life span of AH66F-bearing rats as well as inhibiting leukocyte function-associated antigen-1 (LFA-1)-dependent adhesion of the cells.
Rat ascites hepatoma AH66F is a high malignant tumor line, and AH66F-bearing rats died about 10 d after tumor inoculation. When treated with a protein kinase C (PKC) inhibitor, NA-382, the life span of AH66F-bearing rats was significantly prolonged, while a potent protein kinase A inhibitor, H-89, was not effective. In the adhesion assay, the adhesive ability to the mesentery-derived mesothelial cells (M-cells) of AH66F cells from rats injected with 10 mg/kg of NA-382 was significantly decreased, while the adhesion rate of the cells from the vehicle control group and from the H-89 (10 mg/kg)-treated group was about 50%. The adhesion of AH66F cells from the vehicle control group was curtailed to one half by leukocyte function-associated antigen-1 (LFA-1) beta-chain monoclonal antibody (WT.3), but that from the NA-382 group was not further influenced by WT.3. In flow cytometric analysis using WT.3, the expression of LFA-1 beta-chain on AH66F cells from the NA-382-treated group was also partially decreased, while that from the H-89-treated group was not changed. It was confirmed in vitro that after treatment with these protein kinase inhibitors for 48 h the expression of LFA-1 beta-chain in the cells was decreased by NA-382, but not by H-89. These results suggested that the PKC inhibitor prolongs the life span of AH66F-bearing rats through inhibition of LFA-1-dependent adhesion of the cells.
Nomura
M
M
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Sugiura
N
N
Miyamoto
K
K
D000470:Alkaloids / Q000627:therapeutic use*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D008017:Life Expectancy; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D004791:Enzyme Inhibitors; D016169:Lymphocyte Function-Associated Antigen-1; C075317:N-ethoxycarbonyl-7-oxostaurosporine; D011493:Protein Kinase C; D019311:Staurosporine