An inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine(H-7) inhibits TPA-induced reduction of vincristine uptake from P388 murine leukemic cell.

The effects of protein kinase C inhibitor H-7 (1-(5-isoquinolinylsulfonyl)-2-methylpiperazine) on tumor-promoting phorbol ester induced inhibition of vincristine uptake in P388 murine leukemic cells were investigated with the objective of assessing the possible role of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) in vincristine uptake. 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a potent inhibitor at concentrations above 1 nM. Other phorbol esters also inhibited vincristine uptake in approximate proportion to their activity in competing for [20-3H]phorbol 12,13-dibutrate binding. TPA enhanced the Ca2+-activated, phospholipid-dependent phosphorylation of histone III-S by a soluble protein fraction of cells. Phosphorylation of various cell lysate proteins (p18, p21, p29, p34 and p45) were also stimulated by TPA. These TPA-induced stimulations were also inhibited dose-dependently by H-7. It is tentatively concluded that the phosphorylation of cell lysate protein substrates by protein kinase C may be an important mechanism linked to the regulation of vincristine uptake in leukemic cell.