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-tetradecanoylphorbol-13-acetate (TPA) on cisplatin cytotoxicity was examined in a human osteosarcoma U2-OS cell line and in a U2-OS variant (U2-OS/Pt) selected after continuous exposure to increasing concentrations of cisplatin. U2-OS/Pt cells showed a 7.5-fold resistance to the drug. A 24 h exposure of cells to TPA caused a potentiation of cisplatin cytotoxicity in sensitive and in resistant cells; under these conditions, PKC activity was shown to be down-regulated. In contrast, a short-term exposure of cells to TPA did not affect cisplatin cytotoxicity in U2-OS or in U2-OS/Pt cells. These results support the involvement of PKC in cellular response to cisplatin. However, this enzyme is probably not directly implicated in the mechanisms of acquired resistance in this cell system.
Perego
P
P
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Casati
G
G
Gambetta
R A
RA
Soranzo
C
C
Zunino
F
F
D002945:Cisplatin / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin