EFFECT OF MODULATION OF PROTEIN-KINASE-C ACTIVITY ON CISPLATIN CYTOTOXICITY IN CISPLATIN-RESISTANT AND CISPLATIN-SENSITIVE HUMAN OSTEOSARCOMA CELLS

The effect of modulation of protein kinase C (PKC) activity by 12-O-te tradecanoylphorbol-13-acetate (TPA) on cisplatin cytotoxicity was exam ined in a human osteosarcoma U2-OS cell line and in a U2-OS variant (U 2-OS/Pt) selected after continuous exposure to increasing concentratio ns of cisplatin. U2-OS/Pt cells showed a 7.5-fold resistance to the dr ug. A 24 h exposure of cells to TPA caused a potentiation of cisplatin cytotoxicity in sensitive and in resistant cells; under these conditi ons, PKC activity was shown to be down-regulated. In contrast, a short -term exposure of cells to TPA did not affect cisplatin cytotoxicity i n U2-OS or in U2-OS/Pt cells. These results support the involvement of PKC in cellular response to cisplatin. However, this enzyme is probab ly not directly implicated in the mechanisms of acquired resistance in this cell system.